Professional Documents
Culture Documents
Hua YIN
1|
CPH training | May 2016
Stability –purpose
Provide evidence of how the quality of an API or FPP varies with time
under the influence of a variety of environmental factors such as
temperature, humidity and light
2|
CPH training | May 2016
Stability –purpose
Select packaging
3|
CPH training | May 2016
References
Generics Guideline (TRS 970 annex 4, section 3.2.S.7 and 3.2.P.8)
Stability Testing of APIs and FPPs -- WHO Stability Guide in TRS953
(2009) Annex 2:
ICH Q1(A, B, C, D and E)
FDC guideline-- TRS 929 Annex 5 (appendix 3, Table A.1)
For PQTm, when there are contradictions, the Generic guideline prevails
Lynda Paleshnuik. Annual Prequalification Assessment Training.
Copenhagen, 2010 & 2015
4|
CPH training | May 2016
Overview
5|
CPH training | May 2016
Stress Studies
6|
CPH training | May 2016
Stress testing
7|
CPH training | May 2016
Stress testing
8|
CPH training | May 2016
API stability
Stress testing – Typical Stress conditions
9|
CPH training | May 2016
Stress Studies
10 |
CPH training | May 2016
Stress studies:
Approach for Assessment: DO
Check if data is provided, either generated by
supplier/applicant or from literature references
11 |
CPH training | May 2016
Stress studies:
Approach for Assessment : DON’T
12 |
CPH training | May 2016
Photostability Studies
API
Exposed
FPP
FPP in
package
13 |
CPH training | May 2016
Photostability Studies
14 |
CPH training | May 2016
Overview
15 |
CPH training | May 2016
Stability protocol
Conditions of storage
Testing frequency
16 |
CPH training | May 2016
Selection of Batches (PQTm)
17 |
CPH training | May 2016
Container closure system (s)
Each strength and container type, pack size should be studied unless
bracketing/matrixing is applied.
The storage orientation of the product, i.e. upright versus inverted, may
need to be included in a protocol when contact of the product with the
closure system may be expected to affect the stability of the products
contained.
18 |
CPH training | May 2016
Storage Conditions
Climatic Zones
Zone I: 21°C/45% RH
Zone II: 25°C/60% RH (subtropical)
Zone III: 30°C/35% RH (hot/ dry)
Zone IVA: 30°C/65% RH (hot/ humid)
Zone IVB: 30°C/75% RH (hot/ very humid)
PQTm:
Long term stability studies should cover all climatic zones if possible, i.e
30°C± 2°C/75% ± 5% RH
Accelerated stability studies: 40°C± 2°C/75% ± 5% RH
* See ICH Q1 for conditions of storage in a refrigerator or a freezer
19 |
CPH training | May 2016
Testing Frequency
For PQTm, when long tem condition is Zone IV, there is no intermediate
condition
20 |
CPH training | May 2016
Minimum data requirements at time of submission
Intermediate * * *
21 |
CPH training | May 2016
Stability-indicating quality parameters
Microbiological testing
Other tests for specific dosage forms, e.g. pH, clarity, particulate matter (for
solutions), fineness of dispersion (for dispersible tablets), sterility (for
parenterals), reconstitution time for powders
22 |
CPH training | May 2016
Non Stability-indicating quality parameters
Identity
Content uniformity
Diameter/thickness
Residual solvents
Average weight
23 |
CPH training | May 2016
What are expected in the stability reports?
General information: Product name, manufacturing sites, date of
manufacturing; batch number, batch size, strength, container/clourse (seals,
desiccants should be identified)
Evaluation
– Justify parameters tested (OoS, OoT discussion)
– Statistical analysis, if necessary
Conclusions
– Proposed retest period or shelf-Life
– Proposed storage condition
24 |
CPH training | May 2016
Overview
25 |
CPH training | May 2016
Evaluation of Stability Data
Review the protocol and report, confirm the number of batches, batch
size, packaging, storage conditions, test frequencies, specification.
Review the stability results (details follow)
Notes: Stability of the FPP is product-dependent, not solely due to the API
stability. Proceed with caution.
26 |
CPH training | May 2016
Evaluation of Stability Data
27 |
CPH training | May 2016
Evaluation of Stability Data
Storage conditions Strength and batch Batch size Container closure Completed (and
(◦C, % RH) number system proposed) test intervals
Date of mfg: X95910- Nov 2009, X05172 –Dec 2009, X85110 - Mar 2008
28 |
CPH training | May 2016
Evaluation of Stability Data
Summary of the stability results observed for the above accelerated and long-term
studies:
Test Results
Description
Moisture
Impurities
Assay
Dissolution
etc.
29 |
CPH training | May 2016
Evaluation of Stability Data
Summary of the stability results
etc…
Note: When summarizing, the limits should be included in the stability summary
30 |
CPH training | May 2016
Evaluation of Stability Data
31 |
CPH training | May 2016
Summarizing impurities/degradants
Focus on the first digit after the decimal point, i.e. 0.X%, variability on the
second digit after decimal point is not critical, e.g. 0.02% Vs 0.07% may
not indicate an increasing trend due to the variability of method.
32 |
CPH training | May 2016
Summarizing dissolution data
33 |
CPH training | May 2016
Summarizing dissolution data
Example:
Test Results
S1: each unit ≥ Q+5% (80%) Are the summarized values individual or average
values?
S2: Ave ≥ Q (75%) , no unit < Q-15% (60%) Does this meet the stage 1 limits?
S3: Ave ≥ Q (75%) , NMT 2 units < Q-15% (60%) ,
no unit < Q-25% (50%)
34 |
CPH training | May 2016
Summarizing dissolution data
or, the range of individual results + average results for each station
(e.g. individual 82-94, ave. 88)
35 |
CPH training | May 2016
Summarizing dissolution data
Example:
Test Results
36 |
CPH training | May 2016
Overview
37 |
CPH training | May 2016
Trends, Significant changes, OoS
Variation: means you won’t usually have a perfect linear trend (analytical
variability, sample uniformity)
Trends: if the majority of stations show a trend (downward, upward),
consider it a trend.
OOT: analytical value outside our experience but within the specification (no
OOS)
OOS: analytical value outside of the registered specification
38 |
CPH training | May 2016
“Significant Change”
For an API: "significant change" is failure to meet the specification for any
parameter
39 |
CPH training | May 2016
Extrapolation
Extrapolation: Extend the retest period or shelf life beyond the period
covered by available long-term stability data
40 |
CPH training | May 2016
Extrapolation
ICH Q1E –extrapolation without statistical analysis
41 |
CPH training | May 2016
Extrapolation
42 |
CPH training | May 2016
Extrapolation
For products for zone IVB, extrapolation should be done cautiously. ICH
Q1 guidance is for zone II (25C/60%), where there is intermediate data to
consider and provide additional assurance.
43 |
CPH training | May 2016
In case significant changes are observed
Stability is complex and must be considered case-by-case, but various
considerations can be weighed to help make a decision, including:
extent of change
“Significant changes” that are not failures, e.g. Assay decrease from
100% to 94.0%;
Marginal failures, e.g. 89.6% assay for 90.0-110.0% limit;
Catastrophic failures, e.g. 70% assay, 20% degradation
packaging involved
44 |
CPH training | May 2016
In case significant changes are observed
Possible responses:
No allowed extrapolation
45 |
CPH training | May 2016
Evaluation of Stability Data
Tabulate and/or plot stability data on all attributes at all storage conditions
and evaluate each attribute separately
Refer to ICH Q1E appendix A decision Tree for Retest period or shelf life
Estimation
46 |
CPH training | May 2016
Example #1
47 |
CPH training | May 2016
Example #1
Approach: Accelerated data are not only to support extrapolation, they are
also to cover excursions outside the long-term storage conditions.
Accelerated data are always required to support a retest or shelf-life
period.
48 |
CPH training | May 2016
Example #2
49 |
CPH training | May 2016
Example #2
Answer:
A provisional shelf-life of 24 months (12 months + 12 months) can be
assigned.
Storage statement “Do not store above 30◦C”.
Commitment to continue the statility study should be provided
50 |
CPH training | May 2016
Example #3
51 |
CPH training | May 2016
Example #3
Answer:
A shelf-life of 18 months can be assigned. The shelf-life is
based on real time data due to significant change observed
at accelerated conditions.
Storage statement “Do not store above 30◦C”.
Commitment to charge additional batches to stability studies
52 |
CPH training | May 2016
53 |
CPH training | May 2016