Guidance for Industry   Q1A(R2) Stability Testing of New Drug Substances and Products

If long-term studies are condcuted 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.

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

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

Drug products packaged in impermeable containers (2.2.7.2)

Sensitivity to moisture or potential for solvent loss is not a concern for drug products packaged in impermeable containers that provide a permanent barrier to passage of moisture or solvent. Thus, stability studies for products stored in impermeable containers can be conducted under any controlled or ambient humidity condition.

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Drug products packaged in semipermeable containers (2.2.7.3)

Aqueous-based products packaged in semipermeable containers should be evaluated for potential water loss in addition to physical, chemical, biological, and microbiological stability. This evaluation can be carried out under conditions of low relative humidity, as discussed below. Ultimately, it should be demonstrated that aqueous-based drug products stored in semipermeable containers can withstand low relative humidity environments. Other comparable approaches can be developed and reported for nonaqueous, solvent-based products.

It is up to the applicant to decide whether long-term stability sturdies are performed at 25°C ± 2°C/40% RH ± 5% RH or 30°C ± 2°C/35% RH ± 5% RH.

If 30°C ± 2°C/35% RH ± 5% RH is the long-term condition, there is no intermediate condition.

When long-term studies are conducted at 25°C ± 2°C/40% RH ± 5% RH and significant change other than water loss occurs during the 6 months’ testing at the accelerated storage condition, additional testing at the intermediate storage condition should be performed, as described under the general case, to evaluate the temperature effect at 30°C. A significant change in water loss alone at the accelerated storage condition does not necessitate testing at the intermediate storage condition. However, data should be provided to demonstrate that the drug product will not have significant water loss throughout the proposed shelf life if stored at 25°C and the reference relative humidity of 40 percent RH.

A 5 percent loss in water from its initial value is considered a significant change for a product packaged in a semipermeable container after an equivalent of 3 months’ storage at 40°C/NMT 25 percent RH. However, for small containers (1 mL or less) or unit-dose products, a water loss of 5 percent or more after an equivalent of 3 months’ storage at 40°C/NMT 25 percent RH may be appropriate if justified.

An alternative approach to studying at the reference relative humidity as recommended in the table above (for either long-term or accelerated testing) is performing the stability studies under higher relative humidity and deriving the water loss at the reference relative humidity through calculation. This can be achieved by experimentally determining the permeation coefficient for the container closure system or, as shown in the example below, using the calculated ratio of water loss rates between the two humidity conditions at the same temperature. The permeation

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coefficient for a container closure system can be experimentally determined by using the worst case scenario (e.g., the most diluted of a series of concentrations) for the proposed drug product.

Example of an approach for determining water loss:

For a product in a given container closure system, container size, and fill, an appropriate approach for deriving the water loss rate at the reference relative humidity is to multiply the water loss rate measured at an alternative relative humidity at the same temperature by a water loss rate ratio shown in the table below. A linear water loss rate at the alternative relative humidity over the storage period should be demonstrated.

For example, at a given temperature (e.g., 40°C), the calculated water loss rate during storage at NMT 25 percent RH is the water loss rate measured at 75 percent RH multiplied by 3.0, the corresponding water loss rate ratio.

Valid water loss rate ratios at relative humidity conditions other than those shown in the table above can also be used.

Drug products intended for storage in a refrigerator (2.2.7.4)

If the drug product is packaged in a semipermeable container, appropriate information should be provided to assess the extent of water loss.

Data from refrigerated storage should be assessed according to the evaluation section of this guidance, except where explicitly noted below.

If significant change occurs between 3 and 6 months’ testing at the accelerated storage condition, the proposed shelf life should be based on the real time data available from the long-term storage condition.

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If significant change occurs within the first 3 months’ testing at the accelerated storage condition, a discussion should be provided to address the effect of short-term excursions outside the label storage condition (e.g., during shipment and handling). This discussion can be supported, if appropriate, by further testing on a single batch of the drug product for a period shorter than 3 months but with more frequent testing than usual. It is considered unnecessary to continue to test a product through 6 months when a significant change has occurred within the first 3 months.

Drug products intended for storage in a freezer (2.2.7.5)

For drug products intended for storage in a freezer, the shelf life should be based on the real time data obtained at the long-term storage condition. In the absence of an accelerated storage condition for drug 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.

Drug products intended for storage below -20°C (2.2.7.6)

Drug products intended for storage below -20°C should be treated on a case-by-case basis.

Stability Commitment (2.2.8)

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.

Where the submission includes long-term stability data from three production batches covering the proposed shelf life, a postapproval commitment is considered unnecessary. Otherwise, one of the following commitments should be made:

If the submission includes data from stability studies on at least 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.

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.

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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.

The stability protocol used for studies on commitment batches should be the same as that for the primary batches, unless otherwise scientifically justified.

Where intermediate testing is called for by a significant change at the accelerated storage condition for the primary batches, testing on the commitment batches can be conducted at either the intermediate or the accelerated storage condition. However, if significant change occurs at the accelerated storage condition on the commitment batches, testing at the intermediate storage condition should also be conducted.

Evaluation (2.2.9)

A systematic approach should be adopted in the presentation and evaluation of the stability information, which should include, as appropriate, results from the physical, chemical, biological, and microbiological tests, including particular attributes of the dosage form (e.g., dissolution rate for solid oral dosage forms).

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

Where the data show so little degradation and so little variability that it is apparent from looking at the data that the requested shelf life will be granted, it is normally unnecessary to go through the formal statistical analysis; providing a justification for the omission should be sufficient.

An approach for analyzing data of a quantitative attribute that is expected to change with time is to determine the time at which the 95 percent one-sided confidence limit for the mean curve intersects the acceptance criterion. If analysis shows that the batch-to-batch variability is small, it is advantageous to combine the data into one overall estimate. This can be done by first applying appropriate statistical tests (e.g., p values for level of significance of rejection of more than 0.25) to the slopes of the regression lines and zero time intercepts for the individual batches. If it is inappropriate to combine data from several batches, the overall shelf life should be based on the minimum time a batch can be expected to remain within acceptance criteria.

The nature of the degradation relationship will determine whether the data should be transformed for linear regression analysis. Usually the relationship can be represented by a linear, quadratic, or cubic function on an arithmetic or logarithmic scale. Statistical methods should be employed to test the goodness of fit on all batches and combined batches (where appropriate) to the assumed degradation line or curve.

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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. This justification should be based, for example, 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/or existence of supporting stability data. However, this extrapolation assumes that the same degradation relationship will continue to apply beyond the observed data.

Any evaluation should consider not only the assay but also the degradation products and other appropriate attributes. Where appropriate, attention should be paid to reviewing the adequacy of the mass balance and different stability and degradation performance.

Statements/Labeling (2.2.10)

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. 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.

There should be a direct link between the label storage statement and the demonstrated stability of the drug product. An expiration date should be displayed on the container label.

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GLOSSARY (3)

The following definitions are provided to facilitate interpretation of the guidance.

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. Data from these studies, in addition to long-term stability studies, can be used to assess longer term chemical effects at nonaccelerated conditions and to evaluate the effect of short-term excursions outside the label storage conditions such as might occur during shipping. Results from accelerated testing studies are not always predictive of physical changes.

Bracketing: The design of a stability schedule such that only samples on the extremes of certain design factors (e.g., strength, package size) are tested at all time points as in a full design. The design assumes that the stability of any intermediate levels is represented by the stability of the extremes tested. Where a range of strengths is to be tested, bracketing is applicable if the strengths are identical or very closely related in composition (e.g., for a tablet range made with different compression weights of a similar basic granulation, or a capsule range made by filling different plug fill weights of the same basic composition into different size capsule shells). Bracketing can be applied to different container sizes or different fills in the same container closure system.

Climatic zones: The four zones in the world that are distinguished by their characteristic, prevalent annual climatic conditions. This is based on the concept described by W. Grimm (Drugs Made in Germany, 28:196-202, 1985 and 29:39-47, 1986).

Commitment batches: Production batches of a drug substance or drug product for which the stability studies are initiated or completed postapproval through a commitment made in the registration application.

Container closure system: The sum of packaging components that together contain and protect the dosage form. This includes primary packaging components and secondary packaging components if the latter are intended to provide additional protection to the drug product. A packaging system is equivalent to a container closure system.

Dosage form: A pharmaceutical product type (e.g., tablet, capsule, solution, cream) that contains a drug substance generally, but not necessarily, in association with excipients.

Drug product:   The dosage form in the final immediate packaging intended for marketing.

Drug substance: The unformulated drug substance that may subsequently be formulated with excipients to produce the dosage form.

Excipient:   Anything other than the drug substance in the dosage form.

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Expiration date: The date placed on the container label of a drug product designating the time prior to which a batch of the product is expected to remain within the approved shelf life specification, if stored under defined conditions, and after which it must not be used.

Formal stability studies: Long-term and accelerated (and intermediate) studies undertaken on primary and/or commitment batches according to a prescribed stability protocol to establish or confirm the retest period of a drug substance or the shelf life of a drug product.

Impermeable containers: Containers that provide a permanent barrier to the passage of gases or solvents (e.g., sealed aluminum tubes for semi-solids, sealed glass ampoules for solutions).

Intermediate testing: 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.

Long-term testing: Stability studies under the recommended storage condition for the retest period or shelf life proposed (or approved) for labeling.

Mass balance: The process of adding together the assay value and levels of degradation products to see how closely these add up to 100 percent of the initial value, with due consideration of the margin of analytical error.

Matrixing: The design of a stability schedule such that a selected subset of the total number of possible samples for all factor combinations is tested at a specified time point. At a subsequent time point, another subset of samples for all factor combinations is tested. The design assumes that the stability of each subset of samples tested represents the stability of all samples at a given time point. The differences in the samples for the same drug product should be identified as, for example, covering different batches, different strengths, different sizes of the same container closure system, and, possibly in some cases, different container closure systems.

Mean kinetic temperature: A single derived temperature that, if maintained over a defined period of time, affords the same thermal challenge to a drug substance or drug product as would be experienced over a range of both higher and lower temperatures for an equivalent defined period. The mean kinetic temperature is higher than the arithmetic mean temperature and takes into account the Arrhenius equation.

When establishing the mean kinetic temperature for a defined period, the formula of J. D.

Haynes (J. Pharm. Sci., 60:927-929, 1971) can be used.

New molecular entity: An active pharmaceutical substance not previously contained in any drug product registered with the national or regional authority concerned. A new salt, ester, or noncovalent bond derivative of an approved drug substance is considered a new molecular entity for the purpose of stability testing under this guidance.

Pilot scale batch: A batch of a drug substance or drug product manufactured by a procedure fully representative of and simulating that to be applied to a full production scale batch. For

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solid oral dosage forms, a pilot scale is generally, at a minimum, one-tenth that of a full production scale or 100,000 tablets or capsules, whichever is larger.

Primary batch: A batch of a drug substance or drug product used in a formal stability study, from which stability data are submitted in a registration application for the purpose of establishing a retest period or shelf life, respectively. A primary batch of a drug substance should be at least a pilot scale batch. For a drug product, two of the three batches should be at least pilot scale batch, and the third batch can be smaller if it is representative with regard to the critical manufacturing steps. However, a primary batch may be a production batch.

Production batch: A batch of a drug substance or drug product manufactured at production scale by using production equipment in a production facility as specified in the application.

Retest date: The date after which samples of the drug substance should be examined to ensure that the material is still in compliance with the specification and thus suitable for use in the manufacture of a given drug product.

Retest period: The period of time during which the drug substance is expected to remain within its specification and, therefore, can be used in the manufacture of a given drug product, provided that the drug substance has been stored under the defined conditions. After this period, a batch of drug substance destined for use in the manufacture of a drug product should be retested for compliance with the specification and then used immediately. A batch of drug substance can be retested multiple times and a different portion of the batch used after each retest, as long as it continues to comply with the specification. For most biotechnological/biological substances known to be labile, it is more appropriate to establish a shelf life than a retest period. The same may be true for certain antibiotics.

Semipermeable containers: Containers that allow the passage of solvent, usually water, while preventing solute loss. The mechanism for solvent transport occurs by absorption into one container surface, diffusion through the bulk of the container material, and desorption from the other surface. Transport is driven by a partial pressure gradient. Examples of semipermeable containers include plastic bags and semirigid, low-density polyethylene (LDPE) pouches for large volume parenterals (LVPs), and LDPE ampoules, bottles, and vials.

Shelf life (also referred to as expiration dating period): The time period during which a drug product is expected to remain within the approved shelf life specification, provided that it is stored under the conditions defined on the container label.

Specification:   See ICH Q6A and Q6B.

Specification, Release: The combination of physical, chemical, biological, and microbiological tests and acceptance criteria that determine the suitability of a drug product at the time of its release.

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Specification, Shelf life: The combination of physical, chemical, biological, and microbiological tests and acceptance criteria that determine the suitability of a drug substance throughout its retest period, or that a drug product should meet throughout its shelf life.

Storage condition tolerances: The acceptable variations in temperature and relative humidity of storage facilities for formal stability studies. The equipment should be capable of controlling the storage condition within the ranges defined in this guidance. The actual temperature and humidity (when controlled) should be monitored during stability storage. Short-term spikes due to opening of doors of the storage facility are accepted as unavoidable. The effect of excursions due to equipment failure should be addressed and reported if judged to affect stability results. Excursions that exceed the defined tolerances for more than 24 hours should be described in the study report and their effect assessed.

Stress testing (drug substance): Studies undertaken to elucidate the intrinsic stability of the drug substance. Such testing is part of the development strategy and is normally carried out under more severe conditions than those used for accelerated testing.

Stress testing (drug product): Studies undertaken to assess the effect of severe conditions on the drug product. Such studies include photostability testing (see ICH Q1B) and specific testing of certain products (e.g., metered dose inhalers, creams, emulsions, refrigerated aqueous liquid products).

Supporting data: Data, other than those from formal stability studies, that support the analytical procedures, the proposed retest period or shelf life, and the label storage statements. Such data inclu de (1) stability data on early synthetic route batches of drug substance, small-scale batches of materials, investigational formulations not proposed for marketing, related formulations, and product presented in containers and closures other than those proposed for marketing; (2) information regarding test results on containers; and (3) other scientific rationales.

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REFERENCES (4)³

ICH Q1B Photostability Testing of New Drug Substances and Products

ICH Q1C Stability Testing for New Dosage Forms

ICH Q3A Impurities in New Drug Substances

ICH Q3B Impurities in New Drug Products

ICH Q5C Quality of Biotechnological Products: Stability Testing of Biotechnological/Biological Products

ICH Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances

and New Drug Products: Chemical Substances

ICH Q6B Specifications: Test Procedures and Acceptance Criteria for New Drug Substances

and New Drug Products: Biotechnological/Biological Products

We update guidances periodically. To make sure you have the most recent version of a guidance, check the CDER guidance page at http://www.fda.gov/cder/guidance/index.htm

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ATTACHMENT

List of Revision 2 Changes

The revisions to this Q1A guidance result from adoption of the ICH guidance Q1F Stability Data Package for Registration Applications in Climatic Zones III and IV. The following changes were made.

The intermediate storage condition has been changed from 30°C ± 2°C/60% RH ± 5% RH to 30°C ± 2°C/65% RH ± 5% RH in the following sections:

II.A.7.a (2.1.7.1)   Drug Substance - Storage Conditions - General case

II.B.7.a (2.2.7.1) Drug Product - Storage Conditions - General case

II.B.7.c (2.2.7.3) Drug products packaged in semipermeable containers

Glossary   (3)Intermediate testing

30°C ± 2°C/65% RH ± 5% RH has been added as a suitable alternative long-term storage condition to 25°C ± 2°C/60% RH ± 5% in the following sections:

II.A.7.a (2.1.7.1) Drug Substance - Storage Conditions - General case

II.B.7.a (2.2.7.1)   Drug Product - Storage Conditions - General case

30°C ± 2°C/35% RH ± 5% RH has been added as a suitable alternative long-term storage condition to 25°C ± 2°C/40% RH ± 5% and the corresponding example for the ratio of water-loss rates has been included in the following section:

II.B.7.c (2.2.7.3) Drug products packaged in semipermeable containers

Midstream switch of the intermediate storage condition from 30°C ± 2°C/60% RH ± 5% RH to 30°C ± 2°C/65% RH ± 5% RH can be appropriate provided that the respective storage conditions and the date of the switch are clearly documented and stated in the registration application.

It is recommended that registration applications contain data from complete studies at the intermediate storage condition 30°C ± 2°C/65% RH ± 5% RH, if applicable, by three years after the date of publication of this revised guideline in the respective ICH tripartite region.