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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Workshop on Planning, conduct and regulatory assessment of stability studies

Accra, Ghana December 2009

Overview
Evaluation/Extrapolation of data
Statements/Labelling
Ongoing Stability Studies

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Workshop on Planning, conduct and regulatory assessment of stability studies

Accra, Ghana December 2009

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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Workshop on Planning, conduct and regulatory assessment of stability studies

Accra, Ghana December 2009

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 APIs and FPPs

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Workshop on Planning, conduct and regulatory assessment of stability studies

Accra, Ghana December 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 APIs, a shelf-life is
given.

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Workshop on Planning, conduct and regulatory assessment of stability studies

Accra, Ghana December 2009

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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Workshop on Planning, conduct and regulatory assessment of stability studies

Accra, Ghana December 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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Workshop on Planning, conduct and regulatory assessment of stability studies

Accra, Ghana December 2009

API Stress Testing

New Guide: should include the effect of:
- temperature, in 10 increments above accelerated (ie
50C, 60C )
- 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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Workshop on Planning, conduct and regulatory assessment of stability studies

Accra, Ghana December 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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Workshop on Planning, conduct and regulatory assessment of stability studies

Accra, Ghana December 2009

API stability
Stress testing
Main Generic guideline 2.7.1 suggested conditions

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Workshop on Planning, conduct and regulatory assessment of stability studies

Accra, Ghana December 2009

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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Workshop on Planning, conduct and regulatory assessment of stability studies

Accra, Ghana December 2009

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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Workshop on Planning, conduct and regulatory assessment of stability studies

Accra, Ghana December 2009

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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Workshop on Planning, conduct and regulatory assessment of stability studies

Accra, Ghana December 2009

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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Workshop on Planning, conduct and regulatory assessment of stability studies

Accra, Ghana December 2009

API Stability Testing

PART TWO

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Workshop on Planning, conduct and regulatory assessment of stability studies

Accra, Ghana December 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.
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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Workshop on Planning, conduct and regulatory assessment of stability studies

Accra, Ghana December 2009

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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Workshop on Planning, conduct and regulatory assessment of stability studies

Accra, Ghana December 2009

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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Workshop on Planning, conduct and regulatory assessment of stability studies

Accra, Ghana December 2009

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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Workshop on Planning, conduct and regulatory assessment of stability studies

Accra, Ghana December 2009

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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Workshop on Planning, conduct and regulatory assessment of stability studies

Accra, Ghana December 2009

Storage Conditions
Requirements at time of submission:
Stable API: (Supplement 2)
6 months at 40C/75%
6 months at 30C/65%
Other API:
6 months at 40C/75%
12 months at 30C/65%
PQP is moving towards long term at 30C/75% being the preferred
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Workshop on Planning, conduct and regulatory assessment of stability studies

Accra, Ghana December 2009

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

21C/45%RH

Zone II: subtropical/mediterranean

25C/60%RH

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

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Zone VIa: hot/humid

30C/65%RH

Zone VIb: hot/very humid

30C/75%RH

Workshop on Planning, conduct and regulatory assessment of stability studies

Accra, Ghana December 2009

Storage Conditions II
When long term data is conducted at 25C/60% and
significant change is observed at accelerated conditions,
data should be provided at intermediate conditions (eg
30C/65%).
Tolerances - The chamber temperature must be
controlled within 2C, and the humidity controlled within
5% relative humidity.

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Workshop on Planning, conduct and regulatory assessment of stability studies

Accra, Ghana December 2009

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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Workshop on Planning, conduct and regulatory assessment of stability studies

Accra, Ghana December 2009

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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Workshop on Planning, conduct and regulatory assessment of stability studies

Accra, Ghana December 2009

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 retest (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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Workshop on Planning, conduct and regulatory assessment of stability studies

Accra, Ghana December 2009

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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Workshop on Planning, conduct and regulatory assessment of stability studies

Accra, Ghana December 2009

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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Workshop on Planning, conduct and regulatory assessment of stability studies

Accra, Ghana December 2009

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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Workshop on Planning, conduct and regulatory assessment of stability studies

Accra, Ghana December 2009

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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Workshop on Planning, conduct and regulatory assessment of stability studies

Accra, Ghana December 2009

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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Workshop on Planning, conduct and regulatory assessment of stability studies

Accra, Ghana December 2009

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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Workshop on Planning, conduct and regulatory assessment of stability studies

Accra, Ghana December 2009