Sunday, October 27, 2019

ICH Q1E- EVALUATION OF STABILITY DATA


1. INTRODUCTION

1.1 Objectives of the Guideline

This guideline is intended to provide recommendations on how to use stability data, generated in accordance with the principles detailed in the ICH guideline “Q1A(R) Stability Testing of New Drug Substances and Products” to propose a retest period or shelf life in a registration application.

This guideline describes when and how extrapolation can be considered when proposing a retest period for a drug substance or a shelf life for a drug product that extends beyond the period covered by “available data from the stability study under the long-term storage condition”.

1.3 Scope of the Guideline

This guideline addresses the evaluation of stability data that should be submitted in registration applications for new molecular entities and associated drug products. The guideline provides recommendations on establishing retest periods and shelf lives for drug substances and drug products intended for storage at or below “room temperature”. It covers stability studies using single- or multi-factor designs and full or reduced designs.

2. GUIDELINES

2.1 General Principles

The purpose of a stability study is to establish, based on testing a minimum of three batches of the drug substance or product, a retest period or shelf life and label storage instructions applicable to all future batches manufactured and packaged under similar circumstances. The degree of variability of individual batches affects the confidence that a future production batch will remain within acceptance criteria throughout its retest period or shelf life.

A systematic approach should be adopted in the presentation and evaluation of the stability information. The stability information should include, as appropriate, results from the physical, chemical, biological, and microbiological tests, including those related to particular attributes of the dosage form (for example, dissolution rate for solid oral dosage forms). The adequacy of the mass balance should be assessed. Factors that can cause an apparent lack of mass balance should be considered, including, for example, the mechanisms of degradation and the stability-indicating capability and inherent variability of the analytical procedures.

The retest period or shelf life proposed should not exceed that predicted for any single attribute.

ICH Q1E guideline mentions about Appendix A and Appendix B guideline, however, in this blog, we are discussing regarding Appendix A i.e. the decision tree which outlines a stepwise approach to stability data evaluation and when and how much extrapolation can be considered for a proposed retest period or shelf life.

2.2 Data presentation
  • Data for all attributes should be presented in an appropriate format (e.g., tabular, graphical, narrative) and an evaluation of such data should be included in the application.
  • The values of quantitative attributes at all time points should be reported as measured (e.g., assay as percent of label claim).
  • If a statistical analysis is performed, the procedure used and the assumptions underlying the model should be stated and justified.
  • A tabulated summary of the outcome of statistical analysis and/or graphical presentation of the long-term data should be included
2.3 Extrapolation

Extrapolation is the practice of using a known data set to infer information about future data. 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. Whether extrapolation of stability data is appropriate depends on the extent of knowledge about the change pattern, the goodness of fit of any mathematical model, and the existence of relevant supporting data. Any extrapolation should be performed such that the extended retest period or shelf life will be valid for a future batch released with test results close to the release acceptance criteria.

2.4 Data Evaluation for Retest Period or Shelf Life Estimation for Drug Substances or Products Intended for Room Temperature Storage

For drug substances or products intended for storage at room temperature, the assessment should begin with any significant change at the accelerated condition and, if appropriate, at the intermediate condition, and progress through the trends and variability of the long-term data. The circumstances are delineated under which extrapolation of retest period or shelf life beyond the period covered by long-term data can be appropriate. A decision tree is provided in Appendix A of ICH Q1E as an aid.

2.4.1 No significant change at accelerated condition

Where no significant change occurs at the accelerated condition, the retest period or shelf life would depend on the nature of the long-term and accelerated data.

2.4.1.1 Long-term and accelerated data showing little or no change over time and little or no variability
  • Where the long-term data and accelerated data for an attribute show little or no change over time and little or no variability, it might be apparent that the drug substance or product will remain well within the acceptance criteria for that attribute during the proposed retest period or shelf life.
  • In these circumstances, a statistical analysis is normally considered unnecessary but justification for the omission should be provided.
  • Justification can include a discussion of the change pattern or lack of change, relevance of the accelerated data, mass balance, and/or other supporting data as described in the parent guideline.
  • 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.
2.4.1.2 Long-term or accelerated data showing change over time and/or variability
  • Where there are differences in stability observed among batches or among other factors (e.g., strength, container size and/or fill) or factor combinations (e.g., strength-by-container size and/or fill) that preclude the combining of data, the proposed retest period or shelf life should not exceed the shortest period supported by any batch, other factor, or factor combination.
  • Alternatively, where the differences are readily attributed to a particular factor (e.g., strength), different shelf lives can be assigned to different levels within the factor (e.g., different strengths).
  • A discussion should be provided to address the cause for the differences and the overall significance of such differences on the product. Extrapolation beyond the period covered by long-term data can be proposed; however, the extent of extrapolation would depend on whether long-term data for the attribute are amenable to statistical analysis.
Data not amenable to statistical analysis

Where long-term data are not amenable to statistical analysis, but relevant supporting data are provided, the proposed retest period or shelf life can be up to one and-a-half times, but should not be more than 6 months beyond, the period covered by long-term data. Relevant supporting data include satisfactory long-term data from development batches that are (1) made with a closely related formulation to, (2) manufactured on a smaller scale than, or (3) packaged in a container closure system similar to, that of the primary stability batches.

Data amenable to statistical analysis

If long-term data are amenable to statistical analysis but no analysis is performed, the extent of extrapolation should be the same as when data are not amenable to statistical analysis. However, if a statistical analysis is performed, it can be appropriate to propose a retest period or shelf life of up to twice, but not more than 12 months beyond, the period covered by long term data, when the proposal is backed by the result of the analysis and relevant supporting data.

2.4.2 Significant change at accelerated condition

Where significant change* occurs at the accelerated condition, the retest period or shelf life would depend on the outcome of stability testing at the intermediate condition, as well as at the long-term condition.

*Note: The following physical changes can be expected to occur at the accelerated condition and would not be considered significant change that calls for intermediate testing if there is no other significant change:
  • Softening of a suppository that is designed to melt at 37ºC, if the melting point is clearly demonstrated,
  • Failure to meet acceptance criteria for dissolution for 12 units of a gelatin capsule or gel-coated tablet if the failure can be unequivocally attributed to cross-linking.
However, if phase separation of a semi-solid dosage form occurs at the accelerated condition, testing at the intermediate condition should be performed. Potential interaction effects should also be considered in establishing that there is no other significant change.


2.4.2.1 No significant change at intermediate condition

If there is no significant change at the intermediate condition, extrapolation beyond the period covered by long-term data can be proposed; however, the extent of extrapolation would depend on whether long-term data for the attribute are amenable to statistical analysis.

Data not amenable to statistical analysis

When the long-term data for an attribute are not amenable to statistical analysis, the proposed retest period or shelf life can be up to 3 months beyond the period covered by long-term data, if backed by relevant supporting data.

Data amenable to statistical analysis

When the long-term data for an attribute are amenable to statistical analysis but no analysis is performed, the extent of extrapolation should be the same as when data are not amenable to statistical analysis. However, if a statistical analysis is performed, the proposed retest period or shelf life can be up to one-and-half times, but should not be more than 6 months beyond, the period covered by long-term data, when backed by statistical analysis and relevant supporting data

Significant change at intermediate condition

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. In addition, a retest period or shelf life shorter than the period covered by long-term data could be called for.

2.5 Data Evaluation for Retest Period or Shelf Life Estimation for Drug Substances or Products Intended for Storage Below Room Temperature

2.5.1 Drug substances or products intended for storage in a refrigerator

Data from drug substances or products intended to be stored in a refrigerator should be assessed according to the same principles as described in Section 2.4 for drug substances or products intended for room temperature storage, except where explicitly noted in the section below. The decision tree in Appendix A of ICH Q1E can be used as an aid.

2.5.1.1 No significant change at accelerated condition

If the long-term and accelerated data show little change over time and little variability, the proposed retest period or shelf life can be up to one-and-a-half times, but should not be more than 6 months beyond, the period covered by long-term data normally without the support of statistical analysis.

Where the long-term or accelerated data show change over time and/or variability, the proposed retest period or shelf life can be up to 3 months beyond the period covered by long-term data if (1) the long-term data are amenable to statistical analysis but a statistical analysis is not performed, or (2) the long-term data are not amenable to statistical analysis but relevant supporting data are provided.

Where the long-term or accelerated data show change over time and/or variability, the proposed retest period or shelf life can be up to one-and-a-half times, but should not be more than 6 months beyond, the period covered by long-term data if (1) the longterm data are amenable to statistical analysis and a statistical analysis is performed, and (2) the proposal is backed by the result of the analysis and relevant supporting data.

2.5.1.2 Significant change at accelerated condition

If significant change occurs between 3 and 6 months’ testing at the accelerated storage condition, the proposed retest period or shelf life should be based on the longterm data. Extrapolation is not considered appropriate. In addition, a retest period or shelf life shorter than the period covered by long-term data could be called for. If the long-term data show variability, verification of the proposed retest period or shelf life by statistical analysis can be appropriate.

If significant change occurs within the first 3 months’ testing at the accelerated storage condition, the proposed retest period or shelf life should be based on long-term data. Extrapolation is not considered appropriate. A retest period or shelf life shorter than the period covered by long-term data could be called for. If the long-term data show variability, verification of the proposed retest period or shelf life by statistical analysis can be appropriate. In addition, a discussion should be provided to address the effect of short-term excursions outside the label storage condition (e.g., during shipping or handling). This discussion can be supported, if appropriate, by further testing on a single batch of the drug substance or product at the accelerated condition for a period shorter than 3 months.

2.5.2 Drug substances or products intended for storage in a freezer

For drug substances or products intended for storage in a freezer, the retest period or shelf life should be based on long-term data. In the absence of an accelerated storage condition for drug substances or products intended to be stored in a freezer, testing on a single batch at an elevated temperature (e.g., 5°C ± 3°C or 25°C ± 2°C) for an appropriate time period should be conducted to address the effect of short-term excursions outside the proposed label storage condition (e.g., during shipping or handling).

2.5.3 Drug substances or products intended for storage below -20°C

For drug substances or products intended for storage below -20°C, the retest period or shelf life should be based on long-term data and should be assessed on a case-by-case basis.

Sr. no.
Storage Conditions
Stability type
Temperature Conditions
Type of change
Shelf life or Retest period
01.
Room Temperature Storage
ACC
40°C ± 2°C/75% RH ± 5% RH
Little or no change
The proposed retest period or shelf life can be up to twice, but should not be more than 12 months beyond

Y= up to 2X, but not exceeding X + 12 months
ACC
40°C ± 2°C/75% RH ± 5% RH
Significant change
The retest period or shelf life would depend on the outcome of stability testing at the intermediate condition, as well as at the long-term condition.
INT
30°C ± 2°C/65% RH ± 5% RH
No change
The proposed retest period or shelf life can be up to 3 months beyond the period covered by long-term data, if backed by relevant supporting data.
INT
30°C ± 2°C/65% RH ± 5% RH
Significant change
Should not exceed the period covered by long-term data
LT
25°C ± 2°C/60% RH ± 5% RH
Little or no change
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.
Y = up to 2X, but not exceeding X + 12 months
LT
25°C ± 2°C/60% RH ± 5% RH
Significant change
The proposed retest period or shelf life can be up to one and-a-half times, but should not be more than 6 months beyond, the period covered by long-term data.
Y = up to 1.5X, but  not exceeding X + 6 months
02.
Refrigerator storage
ACC & LT
25°C ± 2°C/60% RH ± 5% RH
&
5°C ± 3°C
Little change
The proposed retest period or shelf life can be up to one-and-a-half times, but should not be more than 6 months beyond, the period covered by long-term data normally without the support of statistical analysis.
Y = up to 1.5X, but not  exceeding X + 6 months
ACC & LT
25°C ± 2°C/60% RH ± 5% RH
&
5°C ± 3°C
Change
If there is change in long-term data, then
Y = up to X + 3 months.

If there is no change in long-term data then,
Y = up to 1.5X, but not exceeding X + 6 months
ACC
25°C ± 2°C/60% RH ± 5% RH
Significant change
If significant change occurs between 3 and 6 months’ testing at the accelerated storage condition, the proposed retest period or shelf life should be based on the long term data.
03.
Freezer
LT
N.A.
N.A.
The retest period or shelf life should be based on long-term data
04.
Below -20°C

LT
N.A.
N.A.
The retest period or shelf life should be based on long-term data and should be assessed on a case-by-case basis

ACC- Accelerated stability
INT- Intermediate stability
LT- Long-term stability
N.A.- Not applicable

Note: For drug substances or products intended to be stored in a freezer, accelerated storage testing should be performed for single batch at an elevated temperature (e.g., 5°C ± 3°C or 25°C ± 2°C) for an appropriate time period to address the effect of short-term excursions outside the proposed label storage condition (e.g., during shipping or handling).

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