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
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
Overview
 Evaluation
 Statements/Labelling
 Ongoing Stability Studies
 Common Deficiencies
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
Stability Assessment
References

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…
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
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)
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
Stability Assessment
References
4) 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.
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
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 containerclosure system.
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
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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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
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.
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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.
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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
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
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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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
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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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
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
 See the Main Generic guideline 2.7.1 for suggested
conditions (heat, humidity, acid/base, oxidative, photo,
metal ions).
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
Stress studies:
Approach for Assessment
Do:
-
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 1030% = adequate degradation)
-
Confirm the stability-indication of methods where intended (ie mass balance,
peak homogeneity)
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
Stress studies:
Approach
Don’t:
- 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.
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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.
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
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)
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
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.
Methods:
- If same as in API specs, cross-reference
- If different, provide validation data for impurity/degradant and
assay methods
- methods should be stability-indicating
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
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.
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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.
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
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
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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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%
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
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.
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
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
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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.
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API Stability
Stability 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.
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API 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. See
New Guide = Q1A 2.1.9.
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API Stability
Evaluation
 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.
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API Stability
Evaluation
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.
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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. [New Guide =
Q1A]
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Example Problem #1
API 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 retest period, which is supported by data, is approved.
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Example problem #2
 12 months long-term data is provided at 25◦C/60%, not 30◦C/65%.
Accelerated/long-term data is acceptable.
Approach:
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.
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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.
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
API Stability
Statements/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.
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
API Stability
Statements/Labelling
 Note: confirm that the re-test/storage on API
specifications is in agreement with that proposed and/or
considered supported by the data.
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
API Stability
Ongoing 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.
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
API Stability
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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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
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.
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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
Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
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.
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
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.
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
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.
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
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.
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
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.
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Questions?
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009