Stability testing & climatic zones

* GCC States are categorized in climatic zones III & IV a. GCC v3.3 (archived) · 2. Glossary – Climatic zone (table footnote)

Long-term 30 °C ± 2 °C/ 65% RH ± 5% RH GCC v3.3 (archived) · 3.2.6.1 General case (FPP table)

Details of the conditions recommended for these stability studies are included in the relevant CHMP/ICH Guidelines where storage conditions for real time studies were chosen as 25°C/60% RH supported by accelerated or, where applicable, intermediate conditions and based on the mean kinetic temperature of climatic zone I/II, the relevant zone for the EU. EMA storage declaration · A. 1. Background

The mean kinetic temperature in any part of the world can be derived from climatic data, and the world can be divided into four climatic zones, I-IV. This guideline addresses climatic zones I and II. ICH Q1A(R2) · 1.3 General Principles

Long term* 25°C ± 2°C/60% RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% RH ICH Q1A(R2) · 2.2.7.1 General case (table)

The mean kinetic temperature in any part of the world can be derived from climatic data, and the world can be divided into four climatic zones, I-IV. This guidance addresses climatic zones I and II. FDA Q1A(R2) · 1.3

Long-term* 25°C ± 2°C/60% RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% RH 12 months FDA Q1A(R2) · 2.2.7.1 (table)

It is up to the applicant to decide whether long-term stability sturdies [sic] are performed at 25°C ± 2°C/60% RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% RH. FDA Q1A(R2) · 2.2.7.1 (table footnote *)

Note: [sic] — “sturdies” is in FDA’s published text.

Whether long-term stability studies are performed at 25 °C ± 2 °C/60% RH ± 5% RH or 30 °C ± 2 °C/65% RH ± 5% RH or 30 °C ± 2 °C/75% RH ± 5% RH is determined by the climatic zone in which the FPP is intended to be marketed. Testing at a more severe long-term condition can be an alternative to storage at 25 °C/60% RH or 30 °C/65% RH. WHO TRS 1010 Annex 10 · 2.2.7.1 General case, table footnote a

Saudi Arabia 30 °C/65% RH¹ WHO zone table 2021 · Table, Regional Office for the Eastern Mediterranean (EMRO), p. 4

United Kingdom 25 °C/60% RH or 30 °C/65% RH¹ WHO zone table 2021 · Table, Regional Office for Europe (EURO), p. 5

United States of America 25 °C/60% RH or 30 °C/65% RH¹ WHO zone table 2021 · Table, Regional Office for the Americas (AMRO), p. 3

1 Information obtained through respective regional harmonization groups (e.g. ASEAN, ICH and GCC) and from official communications from national medicines regulatory authorities to WHO (entries in bold type). WHO zone table 2021 · Table, footnote 1

Accelerated 40 °C ± 2 °C/ 75% RH ± 5% RH 6 months GCC v3.3 (archived) · 3.2.6.1 General case (FPP table)

Accelerated 40 °C ± 2 °C/ 75% RH± 5% RH 6 months GCC v3.3 (archived) · 3.1.7.1 General case (API table)

Accelerated 40°C ± 2°C/75% RH ± 5% RH 6 months ICH Q1A(R2) · 2.2.7.1 General case (table)

Accelerated 40° C ± 2° C/75% RH ± 5% RH 6 months EMA existing actives · 2.2.7.1 General case (table)

Accelerated 40°C ± 2°C/75% RH ± 5% RH 6 months FDA Q1A(R2) · 2.2.7.1 (table)

Accelerated testing: Studies designed to increase the rate of chemical degradation or physical change of a drug substance or drug product by using exaggerated storage conditions as part of the formal stability studies. FDA Q1A(R2) · 3 (Glossary)

Accelerated 40 °C ± 2 °C/75% RH ± 5% RH 6 months WHO TRS 1010 Annex 10 · 2.2.7.1 General case (table)

No intermediate storage condition is specified in the GCC guideline v3.3.

If long-term studies are conducted at 25°C ± 2°C/60% RH ± 5% RH and “significant change” occurs at any time during 6 months’ testing at the accelerated storage condition, additional testing at the intermediate storage condition should be conducted and evaluated against significant change criteria. The initial application should include a minimum of 6 months’ data from a 12-month study at the intermediate storage condition. ICH Q1A(R2) · 2.2.7.1 General case

Intermediate** 30°C ± 2°C/65% RH ± 5% RH 6 months ICH Q1A(R2) · 2.2.7.1 General case (table)

Studies conducted at 30°C/65% RH and designed to moderately increase the rate of chemical degradation or physical changes for a drug substance or drug product intended to be stored long term at 25°C. ICH Q1A(R2) · 3. Glossary – Intermediate testing

Intermediate** 30°C ± 2°C/65% RH ± 5% RH 6 months FDA Q1A(R2) · 2.2.7.1 (table)

If 30°C ± 2°C/65% RH ± 5% RH is the long-term condition, there is no intermediate condition. FDA Q1A(R2) · 2.2.7.1 (table footnote **)

If long-term studies are condcuted [sic] at 25°C ± 2°C/60% RH ± 5% RH and significant change occurs at any time during 6 months’ testing at the accelerated storage condition, additional testing at the intermediate storage condition should be conducted and evaluated against significant change criteria. The initial application should include a minimum of 6 months’ data from a 12-month study at the intermediate storage condition. FDA Q1A(R2) · 2.2.7.1

Note: [sic] — “condcuted” is in FDA’s published text.

Intermediateᵇ 30 °C ± 2 °C/65% RH ± 5% RH 6 months WHO TRS 1010 Annex 10 · 2.2.7.1 General case (table)

If long-term studies are conducted at 25 °C ± 2 °C/60% RH ± 5% RH and “significant change” occurs at any time during 6 months’ testing at the accelerated storage condition, additional testing at the intermediate storage condition should be conducted and evaluated against significant change criteria. In this case the initial application should include a minimum of six months’ data from a 12-month study at the intermediate storage condition. WHO TRS 1010 Annex 10 · 2.2.7.1 General case

If 30 °C ± 2 °C/65% RH ± 5% RH or 30 °C ± 2 °C/75% RH ± 5% RH is the long-term condition, there is no intermediate condition. WHO TRS 1010 Annex 10 · 2.2.7.1 General case, table footnote b

Data from stability studies should be provided on at least three primary batches of the FPP. GCC v3.3 (archived) · 3.2.2 Selection of batches

Two of the three batches should be at least pilot-scale batches and the third one can be smaller, if justified. GCC v3.3 (archived) · 3.2.2 Selection of batches

Minimum time period covered by data at submission Long-term 30 °C ± 2 °C/ 65% RH ± 5% RH 12 months* Accelerated 40 °C ± 2 °C/ 75% RH ± 5% RH 6 months GCC v3.3 (archived) · 3.2.6.1 General case (FPP table)

The long term testing should cover a minimum of 12 months’ duration on at least three primary batches at the time of submission and should be continued for a period of time sufficient to cover the proposed shelf life. ICH Q1A(R2) · 2.2.7 Storage Conditions

Two of the three batches should be at least pilot scale batches and the third one can be smaller, if justified. ICH Q1A(R2) · 2.2.3 Selection of Batches

Accelerated 40°C ± 2°C/75% RH ± 5% RH 6 months ICH Q1A(R2) · 2.2.7.1 General case (table)

Data from stability studies should be provided on at least three primary batches of the drug product. FDA Q1A(R2) · 2.2.3

Two of the three batches should be at least pilot scale batches, and the third one can be smaller if justified. FDA Q1A(R2) · 2.2.3

The long-term testing should cover a minimum of 12 months’ duration on at least three primary batches at the time of submission and should be continued for a period of time sufficient to cover the proposed shelf life. FDA Q1A(R2) · 2.2.7

For FPPs containing new APIs, data from stability studies should be provided on at least three primary batches of each proposed strength of the FPP. Two of the three batches should be at least pilot-scale batches and the third batch can be smaller, if justified (see example below). WHO TRS 1010 Annex 10 · 2.2.3 Selection of batches

At the time of submission, the long-term testing should cover a minimum of six months for FPPs containing existing APIs or 12 months for FPPs containing new APIs and should be continued for a period of time sufficient to cover the proposed shelf life. WHO TRS 1010 Annex 10 · 2.2.7 Storage conditions

Study Storage condition Minimum time period covered by data at submission Intermediateᵇ 30 °C ± 2 °C/65% RH ± 5% RH 6 months Accelerated 40 °C ± 2 °C/75% RH ± 5% RH 6 months WHO TRS 1010 Annex 10 · 2.2.7.1 General case (table, continued)

In the case of conventional dosage forms with APIs that are known to be stable, data from at least two primary batches should be provided. GCC v3.3 (archived) · 3.2.2 Selection of batches

If the product is registered and marketed in the country of origin, at least one of the batches used in submitted stability study should be of a production scale. GCC v3.3 (archived) · 3.2.2 Selection of batches

For generic products that are marketed in the country of origin, long-term stability study supporting the complete proposed shelf-life should be submitted. GCC v3.3 (archived) · 3.2.6.1 General case (table footnote *)

… a) For conventional dosage forms (e.g. immediate release solid dosage forms, solutions) and when the active substances are known to be stable, stability data on at least two pilot scale batches are acceptable. EMA existing actives · 2.2.3 Selection of Batches

… b) For critical dosage forms or when the active substances are known to be unstable, stability data on three primary batches are to be provided. Two of the three batches should be of at least pilot scale, the third batch may be smaller. EMA existing actives · 2.2.3 Selection of Batches

Long term* 25° C ± 2° C/60% RH ± 5% RH or 30° C ± 2° C/65% RH ± 5% RH 6 months (option a) 12 months (option b) Intermediate 30° C ± 2° C/65% RH ± 5% RH 6 months Accelerated 40° C ± 2° C/75% RH ± 5% RH 6 months EMA existing actives · 2.2.7.1 General case (table)

Submit data from three pilot scale batches or two pilot scale batches and one small scale batch. If the size of the pilot scale batch does not follow ICH recommendations, the applicant should provide a justification. FDA ANDA stability 2013 · III (Discussion), item 1

At the time of submission, provide 6 months of data that include accelerated and long-term conditions. FDA recommends following ICH guidelines with respect to utilization of intermediate conditions to support shelf-life. FDA ANDA stability 2013 · III (Discussion), item 2

Two of the three batches should be of at least 10 percent of the proposed production batch or 100,000 finished dosage units, whichever is greater (i.e., pilot scale batches). The third batch can be smaller than the 10 percent of the proposed production batch, but should not be less than 25 percent of the pilot scale batch. FDA ANDA stability Q&A 2014 · II.C, A13 (Oral dosage forms, (a) Tablets/Capsules)

For FPPs containing existing APIs (e.g. generics), data should be provided on not less than two batches of at least pilot scale, or in the case of an uncomplicated³ FPP (e.g. immediate-release solid FPPs (with noted exceptions) or non-sterile solutions), at least one batch of at least pilot scale and a second batch which may be smaller (e.g. for solid oral dosage forms, 25 000 or 50 000 tablets or capsules) of each proposed strength of the FPP. WHO TRS 1010 Annex 10 · 2.2.3 Selection of batches

At the time of submission, the long-term testing should cover a minimum of six months for FPPs containing existing APIs or 12 months for FPPs containing new APIs and should be continued for a period of time sufficient to cover the proposed shelf life. WHO TRS 1010 Annex 10 · 2.2.7 Storage conditions

Study Storage condition Minimum time period covered by data at submission Intermediateᵇ 30 °C ± 2 °C/65% RH ± 5% RH 6 months Accelerated 40 °C ± 2 °C/75% RH ± 5% RH 6 months WHO TRS 1010 Annex 10 · 2.2.7.1 General case (table, continued)

Data from stability studies on at least three primary batches of the API should normally be provided. The batches should be manufactured to a minimum of pilot scale by the same synthesis route as production batches, and using a method of manufacture and procedure that simulates the final process to be used for production batches. GCC v3.3 (archived) · 3.1.3 Selection of batches

For existing active substances that are known to be stable, data from at least two primary batches should be provided. GCC v3.3 (archived) · 3.1.3 Selection of batches

The long-term testing should normally take place over a minimum of 12 months for the number of batches specified in section 3.1.3 at the time of submission, and should be continued for a period of time sufficient to cover the proposed re-test period or shelf-life. For existing substances that are known to be stable, data covering a minimum of six months may be submitted. GCC v3.3 (archived) · 3.1.7 Storage conditions

… a) Stability information from accelerated and long term testing is to be provided on at least two production scale batches manufactured by the same manufacturing (synthetic) route and procedure described in part 3.2.S.2 of the application. The long term testing and accelerated testing should cover a minimum of 6 months duration at the time of submission … EMA existing actives · 2.1.3 Selection of Batches

… b) Stability information from accelerated and long term testing is to be provided on at least three pilot scale batches manufactured by the same manufacturing (synthetic) route and procedure described in part 3.2.S.2 of the application. The long term testing and accelerated testing should cover a minimum of 6 months duration at the time of submission. EMA existing actives · 2.1.3 Selection of Batches

The applicant should specify that the active substance complies with the pharmacopoeial monograph immediately prior to manufacture of the finished product. In this case no stability studies are required on condition that the suitability of the pharmacopoeial monograph has been demonstrated for the particular named source … EMA existing actives · 2.1.1 General (option a)

Data from formal stability studies should be provided on at least three primary batches of the drug substance. The batches should be manufactured to a minimum of pilot scale by the same synthetic route as production batches and using a method of manufacture and procedure that simulates the final process to be used for production batches. FDA Q1A(R2) · 2.1.3

The long-term testing should cover a minimum of 12 months’ duration on at least three primary batches at the time of submission and should be continued for a period of time sufficient to cover the proposed retest period. FDA Q1A(R2) · 2.1.7

Study Storage condition Minimum time period covered by data at submission Long-term* 25°C ± 2°C/60% RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% RH 12 months Intermediate** 30°C ± 2°C/65% RH ± 5% RH 6 months Accelerated 40°C ± 2°C/75% RH ± 5% RH 6 months FDA Q1A(R2) · 2.1.7.1 (table)

Data from stability studies on at least three primary batches of the API should normally be provided. The batches should be manufactured at a minimum of pilot scale by the same synthesis route as production batches, and using a method of manufacture and a procedure that simulates the final process to be used for production batches. WHO TRS 1010 Annex 10 · 2.1.3 Selection of batches

For new APIs, the long-term testing should normally have taken place over a minimum of 12 months for the number of batches specified in section 2.1.3 at the time of submission, and should be continued for a period of time sufficient to cover the proposed retest period or shelf life. For existing APIs, data covering a minimum of six months may be submitted. WHO TRS 1010 Annex 10 · 2.1.7 Storage conditions

Study Storage condition Minimum time period covered by data at submission Accelerated 40 °C ± 2 °C/75% RH ± 5% RH 6 months WHO TRS 1010 Annex 10 · 2.1.7.1 General case (table, continued)

For products with a proposed shelf-life of at least 12 months, the frequency of testing at the long-term storage condition should normally be every three months over the first year, every six months over the second year and annually thereafter throughout the proposed shelf-life (e.g., 0, 3, 6, 9, 12, 18, 24, 36 months). GCC v3.3 (archived) · 3.2.5 Testing frequency

At the accelerated storage condition, a minimum of three time points, including the initial and final time points (e.g. 0, 3 and 6 months), from a six-month study is recommended. GCC v3.3 (archived) · 3.2.5 Testing frequency

For products with a proposed shelf life of at least 12 months, the frequency of testing at the long term storage condition should normally be every 3 months over the first year, every 6 months over the second year, and annually thereafter through the proposed shelf life. ICH Q1A(R2) · 2.2.6 Testing Frequency

At the accelerated storage condition, a minimum of three time points, including the initial and final time points (e.g., 0, 3, and 6 months), from a 6-month study is recommended. ICH Q1A(R2) · 2.2.6 Testing Frequency

For products with a proposed shelf life of at least 12 months, the frequency of testing at the long-term storage condition should normally be every 3 months over the first year, every 6 months over the second year, and annually thereafter through the proposed shelf life. FDA Q1A(R2) · 2.2.6

At the accelerated storage condition, a minimum of three time points, including the initial and final time points (e.g., 0, 3, and 6 months), from a 6-month study is recommended. FDA Q1A(R2) · 2.2.6

When testing at the intermediate storage condition is called for as a result of significant change at the accelerated storage condition, a minimum of four time points, including the initial and final time points (e.g., 0, 6, 9, 12 months), from a 12-month study is recommended. FDA Q1A(R2) · 2.2.6

For products with a proposed shelf life of at least 12 months, the frequency of testing at the long-term storage condition should normally be every three months over the first year, every six months over the second year and annually thereafter throughout the proposed shelf life. WHO TRS 1010 Annex 10 · 2.2.6 Testing frequency

At the accelerated storage condition, a minimum of three time points, including the initial and final time points (e.g. 0, 3 and 6 months), from a six-month study is recommended. WHO TRS 1010 Annex 10 · 2.2.6 Testing frequency

When testing at the intermediate storage condition is called for as a result of significant change at the accelerated storage condition, a minimum of four time points, including the initial and final time points (e.g. 0, 6, 9 and 12 months), from a 12-month study is recommended. WHO TRS 1010 Annex 10 · 2.2.6 Testing frequency

In general “significant change” for an FPP is defined as: 1. A 5% or more change in assay from its initial content of API(s), or failure to meet the acceptance criteria for potency when using biological or immunological procedures. GCC v3.3 (archived) · 2. Glossary – Significant change

2. Any degradation product exceeding its acceptance criterion. 3. Failure to meet the acceptance criteria for appearance, physical attributes and functionality test (e.g. color, phase separation, resuspendability, caking, hardness, dose delivery per actuation). GCC v3.3 (archived) · 2. Glossary – Significant change

Also, as appropriate for the dosage form: 4. Failure to meet the acceptance criterion for pH; or 5. Failure to meet the acceptance criteria for dissolution for 12 dosage units. GCC v3.3 (archived) · 2. Glossary – Significant change

In general, “significant change” for a drug product is defined as: 1. A 5% change in assay from its initial value; or failure to meet the acceptance criteria for potency when using biological or immunological procedures; 2. Any degradation product’s exceeding its acceptance criterion; ICH Q1A(R2) · 2.2.7.1 General case

3. Failure to meet the acceptance criteria for appearance, physical attributes, and functionality test (e.g., color, phase separation, resuspendibility, caking, hardness, dose delivery per actuation); however, some changes in physical attributes (e.g., softening of suppositories, melting of creams) may be expected under accelerated conditions; ICH Q1A(R2) · 2.2.7.1 General case

… and, as appropriate for the dosage form: 4. Failure to meet the acceptance criterion for pH; or 5. Failure to meet the acceptance criteria for dissolution for 12 dosage units. ICH Q1A(R2) · 2.2.7.1 General case

In general, significant change for a drug product is defined as one or more of the following (as appropriate for the dosage form): • A 5 percent change in assay from its initial value, or failure to meet the acceptance criteria for potency when using biological or immunological procedures • Any degradation product’s exceeding its acceptance criterion … FDA Q1A(R2) · 2.2.7.1

Failure to meet the acceptance criteria for appearance, physical attributes, and functionality test (e.g., color, phase separation, resuspendibility, caking, hardness, dose delivery per actuation). However, some changes in physical attributes (e.g., softening of suppositories, melting of creams) may be expected under accelerated conditions. • Failure to meet the acceptance criterion for pH • Failure to meet the acceptance criteria for dissolution for 12 dosage units … FDA Q1A(R2) · 2.2.7.1

In general, “significant change” for an FPP is defined as: –– a change from the initial content of API(s) of 5% or more detected by assay, or failure to meet the acceptance criteria for potency when using biological or immunological procedures; –– any degradation product exceeding its acceptance criterion; WHO TRS 1010 Annex 10 · 2.2.7.1 General case

… failure to meet the acceptance criteria for appearance, physical attributes and functionality test (e.g. colour, phase separation, resuspendability, caking, hardness, dose delivery per actuation). However, some changes in physical attributes (e.g. softening of suppositories, melting of creams, partial loss of adhesion for transdermal products) may be expected under accelerated conditions. WHO TRS 1010 Annex 10 · 2.2.7.1 General case

Also, as appropriate for the dosage form: –– failure to meet the acceptance criterion for pH; or –– failure to meet the acceptance criteria for dissolution for 12 dosage units. WHO TRS 1010 Annex 10 · 2.2.7.1 General case

However, a provisional shelf-life of 24 months may be established provided the following conditions are satisfied: GCC v3.3 (archived) · 3.2.8 Evaluation

The API is known to be stable (not easily degradable). GCC v3.3 (archived) · 3.2.8 Evaluation

Supporting data indicate that similar formulations have been assigned a shelf-life of 24 months or more. GCC v3.3 (archived) · 3.2.8 Evaluation

Stability studies, as outlined above in section 3.1.11, have been performed and no significant changes have been observed. GCC v3.3 (archived) · 3.2.8 Evaluation

The manufacturer will continue to conduct long-term studies until the proposed shelf-life has been covered, and the results obtained will be submitted to the national regulatory authority. GCC v3.3 (archived) · 3.2.8 Evaluation

Extrapolation to extend the retest period or shelf life beyond the period covered by long-term data can be proposed in the application, particularly if no significant change is observed at the accelerated condition. ICH Q1E · 2.3 Extrapolation

Extrapolation of the retest period or shelf life beyond the period covered by long-term data can be proposed. The proposed retest period or shelf life can be up to twice, but should not be more than 12 months beyond, the period covered by long-term data. ICH Q1E · 2.4.1.1

Where significant change occurs at the intermediate condition, the proposed retest period or shelf life should not exceed the period covered by long-term data. ICH Q1E · 2.4.2.2

Extrapolation of the retest period or shelf life beyond the period covered by long-term data can be proposed. The proposed retest period or shelf life can be up to twice as long as, but should not be more than 12 months beyond, the period covered by long-term data. FDA Q1E · 2.4.1.1

Limited extrapolation of the real time data from the long-term storage condition beyond the observed range to extend the shelf life can be undertaken at approval time if justified. FDA Q1A(R2) · 2.2.9

FDA will grant a shelf life period of two times the available long-term data at the time of approval (up to 24 months) following the recommendation of the ICH Q1E Evaluation of Stability Data (ICH Q1E) guidance,7 provided the submitted data are satisfactory, and data evaluation and appropriate commitments are provided in accordance with ICH Q1E. FDA ANDA stability Q&A 2014 · II.A, A5(i,ii)

Limited extrapolation of the long-term data from the long-term storage condition beyond the observed range to extend the shelf life can be undertaken, if justified. This justification should be based on what is known about the mechanisms of degradation, the results of testing under accelerated conditions, the goodness of fit of any mathematical model, batch size and the existence of supporting stability data. However, this extrapolation assumes that the same degradation relationship will continue to apply beyond the observed data (refer to ICH Q1E). WHO TRS 1010 Annex 10 · 2.2.9 Evaluation

30 °C/65% RH (long-term) 40 °C/75% RH (accelerated) “Do not store above 30 °C” GCC v3.3 (archived) · Appendix 2, Table 2 (FPPs)

5 °C ± 3 °C ”Store in a refrigerator (2 °C to 8 °C)” -20 °C ± 5 °C “Store in freezer” GCC v3.3 (archived) · Appendix 2, Table 2 (FPPs)

“Protect from moisture” should be added as applicable. GCC v3.3 (archived) · Appendix 2, Table 2 (footnote b)

25°C/60%RH (long term) 40°C/75%RH (accelerated) or 30°C/65%RH (long term) 40°C/75%RH (accelerated) None*** Do not refrigerate or freeze EMA storage declaration · A. 4. Core storage statements (table)

25°C/60%RH (long term) 30°C/60 or 65%RH (intermediate) or 30°C/65%RH (long term) Do not store above 30°C or Store below 30°C Do not refrigerate or freeze EMA storage declaration · A. 4. Core storage statements (table)

25°C/60%RH (long term) Do not store above 25°C or Store below 25°C Do not refrigerate or freeze EMA storage declaration · A. 4. Core storage statements (table)

A storage statement should be established for the labeling in accordance with relevant national/regional requirements. The statement should be based on the stability evaluation of the drug product. FDA Q1A(R2) · 2.2.10

Where applicable, specific instruction should be provided, particularly for drug products that cannot tolerate freezing. Terms such as ambient conditions or room temperature should be avoided. FDA Q1A(R2) · 2.2.10

There should be a direct link between the label storage statement and the demonstrated stability of the drug product. FDA Q1A(R2) · 2.2.10

Testing condition under which the stability of the FPP has been demonstrated Recommended labelling statementᵃ 25 °C/60% RH (long-term) 40 °C/75% RH (accelerated) “Do not store above 25 °C” 25 °C/60% RH (long-term) 30 °C/65% RH (intermediate, failure during accelerated stability studies) “Do not store above 25 °C”ᵇ 30 °C/65% RH (long-term) 40 °C/75% RH (accelerated) “Do not store above 30 °C”ᵇ 30 °C/75% RH (long-term) 40 °C/75% RH (accelerated) “Do not store above 30 °C” WHO TRS 1010 Annex 10 · Appendix 2, Table A10.2 Recommended labelling statements for finished pharmaceutical products

“Protect from moisture” should be added as applicable. WHO TRS 1010 Annex 10 · Appendix 2, Table A10.2, footnote b

Demonstrated stability at zone II conditions may result in a label storage statement of “Store between 15 and 30 °C” in line with the convention of some zone II regions. A product with such a statement, received in a zone IV country, would be expected to have demonstrated stability at zone IVa or IVb long-term stability conditions. However, when the stability was demonstrated at zone II long-term conditions, the appropriate statement for distribution in a zone IV region would be “Do not store above 25 °C”. WHO TRS 1010 Annex 10 · Appendix 3 Interpretation of storage statements for products approved in climatic zone II when the products are to be distributed in zone IV

When the available long-term stability data on primary batches do not cover the proposed shelf-life granted at the time of approval, a commitment should be made to continue the stability studies post-approval to firmly establish the shelf-life. GCC v3.3 (archived) · 3.2.7 Stability commitment

If the submission does not include stability data on production batches, a commitment should be made to place the first two or three production batches (see section 3.2.2) on long-term stability studies throughout the proposed shelf-life. GCC v3.3 (archived) · 3.2.7 Stability commitment

Unless otherwise justified, at least one batch per year of product manufactured in every strength and every primary packaging type, if relevant, should be included in the stability programme (unless none is produced during that year). GCC v3.3 (archived) · 3.2.12 Ongoing stability studies

When available long term stability data on primary batches do not cover the proposed shelf life granted at the time of approval, a commitment should be made to continue the stability studies post approval in order to firmly establish the shelf life. ICH Q1A(R2) · 2.2.8 Stability Commitment

If the submission includes data from stability studies on fewer than three production batches, a commitment should be made to continue the long term studies through the proposed shelf life and the accelerated studies for 6 months, and to place additional production batches, to a total of at least three, on long term stability studies through the proposed shelf life and on accelerated studies for 6 months. ICH Q1A(R2) · 2.2.8 Stability Commitment (item 2)

If the submission does not include stability data on production batches, a commitment should be made to place the first three production batches on long term stability studies through the proposed shelf life and on accelerated studies for 6 months. ICH Q1A(R2) · 2.2.8 Stability Commitment (item 3)

When available long-term stability data on primary batches do not cover the proposed shelf life granted at the time of approval, a commitment should be made to continue the stability studies postapproval to firmly establish the shelf life. FDA Q1A(R2) · 2.2.8

If the submission includes data from stability studies on fewer than three production batches, a commitment should be made to continue the long-term studies through the proposed shelf life and the accelerated studies for 6 months, and to place additional production batches, to a total of at least three, on long-term stability studies through the proposed shelf life and on accelerated studies for 6 months. FDA Q1A(R2) · 2.2.8

Also, ANDAs and DMFs should include a commitment to place one batch of drug product and drug substance, respectively, into the annual long-term stability program, and to provide stability data in the annual reports. FDA ANDA stability Q&A 2014 · II.E, A7

When the available long-term stability data on primary batches do not cover the proposed shelf life granted at the time of approval, a commitment should be made to continue the stability studies post-approval throughout the proposed shelf life. This is the primary batch stability commitment. WHO TRS 1010 Annex 10 · 2.2.8 Stability commitments

If the submission includes data from stability studies on fewer than three production batches, a commitment should be made to place the next production batches, up to a total of at least three, on long-term stability studies throughout the proposed shelf life and on accelerated studies for six months. This is the production batch stability commitment. WHO TRS 1010 Annex 10 · 2.2.8 Stability commitments

Unless otherwise justified, at least one batch per year of product manufactured in every strength and every primary packaging type, if relevant, should be included in the stability programme (unless none is produced during that year). WHO TRS 1010 Annex 10 · 2.2.13 Ongoing stability studies