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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Training workshop: Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
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)
- Referred to as “New Guide” in this talk.
- Follows ICH Q1A with key differences noted below.
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.
*In exceptional cases, eg for unstable API’s, a shelf-life is given.
If yes, data requirements are reduced, see “storage conditions” below.
- establish degradation pathways and intrinsic stability,
- validate stability-indicating power of methods
- 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).
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.
- 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.
Primary Batches Definition: Batches used in stability studies to establish retest (API) or shelf-life (FPP). [ICH Q1A and New Guide]
*Pilot batches must be of the same synthesis route, and with method of manufacture and procedure with simulates the final process for production batches.
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
The API is low solubility and micronized, and the FPP is low dose (common for RH products). PSD is critical for this API.
Due to the potential for settling of material on storage, stability results for PSD should be provided to address this issue.
Not in Main Guide: Q1A and New Guide state:
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.
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%
The New Guide is in agreement with Q1A, plus:
The actual conditions are determined by the climatic condition under which the API is intended to be stored. (Discussed at end of talk.)
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.
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.
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.
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]
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.
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.
-Extent of data provided (x LT + 6 mo Acc);
-Actual LT storage conditions;
-Batches (all production?), etc.
New Guide (not in Q1A):
Zone I: temperate21◦C/45%RH
Zone II: subtropical/mediterranean25◦C/60%RH
Zone III: hot/dry30◦C/35%RH
Zone VIa: hot/humid (Kenya) 30◦C/65%RH
Zone VIb: hot/very humid30◦C/75%RH
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.
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.
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.
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.
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.