ICH guide line For stability study

ICH Q1A (STABILITY TESTING OF NEW DRUG SUBSTANCE & PRODUCT)


ICH Q1B (PHOTOSTABILITY TESTING FOR NEW DRUG SUBSTANCE & PRODUCT)

ICHQ1C (STABILITY TESTING OF NEW DOSAGE FORM)

ICH Q1E (EVOLUTION OF STABILITY DATA)

ICHQ3A (IMPURITY IN NEW DRUG SUBSTANCE)

ICH Q3B (IMPURITY IN NEW DRUG PRODUCT)

ICH Q5C ( STABILITY TESTING OF BIOTECHNONOLOGICAL/ BIOLOGICAL PRODUCT)

ICH QA2 GUIDE LINE FOR STABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS

STABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS

1. INTRODUCTION

1.1. Objectives of the Guideline

The following guideline is a revised version of the ICH Q1A guideline and defines

the stability data package for a new drug substance or drug product that is

sufficient for a registration application within the three regions of the EC, Japan,

and the United States. It does not seek necessarily to cover the testing for

registration in or export to other areas of the world.

The guideline seeks to exemplify the core stability data package for new drug

substances and products, but leaves sufficient flexibility to encompass the variety

of different practical situations that may be encountered due to specific scientific

considerations and characteristics of the materials being evaluated. Alternative

approaches can be used when there are scientifically justifiable reasons.

1.2. Scope of the Guideline

The guideline addresses the information to be submitted in registration

applications for new molecular entities and associated drug products. This

guideline does not currently seek to cover the information to be submitted for

abbreviated or abridged applications, variations, clinical trial applications, etc.

Specific details of the sampling and testing for particular dosage forms in their

proposed container closures are not covered in this guideline.

Further guidance on new dosage forms and on biotechnological/biological products

can be found in ICH guidelines Q1C and Q5C, respectively.

1.3. General Principles

The purpose of stability testing is to provide evidence on how the quality of a drug

substance or drug product varies with time under the influence of a variety of

environmental factors such as temperature, humidity, and light, and to establish a

re-test period for the drug substance or a shelf life for the drug product and

recommended storage conditions.

The choice of test conditions defined in this guideline is based on an analysis of the

effects of climatic conditions in the three regions of the EC, Japan and the United

States. 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. The principle has been established that

stability information generated in any one of the three regions of the EC, Japan

and the United States would be mutually acceptable to the other two regions,

provided the information is consistent with this guideline and the labeling is in

accord with national/regional requirements.

2. GUIDELINES

2.1. Drug Substance

2.1.1. General

Information on the stability of the drug substance is an integral part of the

systematic approach to stability evaluation.

2.1.2. Stress Testing

Stress testing of the drug substance can help identify the likely degradation

products, which can in turn help establish the degradation pathways and the

intrinsic stability of the molecule and validate the stability indicating power of the

analytical procedures used. The nature of the stress testing will depend on the

individual drug substance and the type of drug product involved.

Stress testing is likely to be carried out on a single batch of the drug substance. It

should include the effect of temperatures (in 10°C increments (e.g., 50°C, 60°C, etc.)

above that for accelerated testing), humidity (e.g., 75% RH or greater) where

appropriate, oxidation, and photolysis on the drug substance. The testing should

also evaluate the susceptibility of the drug substance to hydrolysis across a wide

range of pH values when in solution or suspension. Photostability testing should

be an integral part of stress testing. The standard conditions for photostability

testing are described in ICH Q1B.

Examining degradation products under stress conditions is useful in establishing

degradation pathways and developing and validating suitable analytical

procedures. However, it may not be necessary to examine specifically for certain

degradation products if it has been demonstrated that they are not formed under

accelerated or long term storage conditions.

Results from these studies will form an integral part of the information provided to

regulatory authorities.

2.1.3. Selection of Batches

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, and using a method of manufacture

and procedure that simulates the final process to be used for, production batches.

The overall quality of the batches of drug substance placed on formal stability

studies should be representative of the quality of the material to be made on a

production scale.

Other supporting data can be provided.

2.1.4. Container Closure System

The stability studies should be conducted on the drug substance packaged in a

container closure system that is the same as or simulates the packaging proposed

for storage and distribution.

2.1.5. Specification

Specification, which is a list of tests, reference to analytical procedures, and

proposed acceptance criteria, is addressed in ICH Q6A and Q6B. In addition,

specification for degradation products in a drug substance is discussed in Q3A.

Stability studies should include testing of those attributes of the drug substance

that are susceptible to change during storage and are likely to influence quality,

safety, and/or efficacy. The testing should cover, as appropriate, the physical,

chemical, biological, and microbiological attributes. Validated stability-indicating

analytical procedures should be applied. Whether and to what extent replication

should be performed will depend on the results from validation studies.

2.1.6. Testing Frequency

For long term studies, frequency of testing should be sufficient to establish the

stability profile of the drug substance. For drug substances with a proposed re-test

period 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 re-test period.

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. Where an expectation (based on development experience) exists

that results from accelerated studies are likely to approach significant change

criteria, increased testing should be conducted either by adding samples at the

final time point or by including a fourth time point in the study design.

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.

2.1.7. Storage Conditions

In general, a drug substance should be evaluated under storage conditions (with

appropriate tolerances) that test its thermal stability and, if applicable, its

sensitivity to moisture. The storage conditions and the lengths of studies chosen

should be sufficient to cover storage, shipment, and subsequent use.

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 re-test period. Additional data

accumulated during the assessment period of the registration application should

be submitted to the authorities if requested. Data from the accelerated storage

condition and, if appropriate, from the intermediate storage condition can be used

to evaluate the effect of short term excursions outside the label storage conditions

(such as might occur during shipping).

Long term, accelerated, and, where appropriate, intermediate storage conditions

for drug substances are detailed in the sections below. The general case applies if

the drug substance is not specifically covered by a subsequent section. Alternative

storage conditions can be used if justified.

2.1.7.1. General case

Study Storage condition Minimum time period covered

by data at submission

Long term 25°C ± 2°C/60% RH ± 5% RH 12 months

Intermediate 30°C ± 2°C/60% RH ± 5% RH 6 months

Accelerated 40°C ± 2°C/75% RH ± 5% RH 6 months

When “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.

Testing at the intermediate storage condition should include all tests, unless

otherwise justified. The initial application should include a minimum of 6 months’

data from a 12-month study at the intermediate storage condition.

“Significant change” for a drug substance is defined as failure to meet its

specification.

2.1.7.2. Drug substances intended for storage in a refrigerator

Study Storage condition Minimum time period covered

by data at submission

Long term 5°C ± 3°C 12 months

Accelerated 25°C ± 2°C/60% RH ± 5% RH 6 months

Data from refrigerated storage should be assessed according to the evaluation

section of this guideline, except where explicitly noted below.

If significant change occurs between 3 and 6 months’ testing at the accelerated

storage condition, the proposed re-test period should be based on the real time

data available at the long term storage condition.

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 shipping or

handling. This discussion can be supported, if appropriate, by further testing on a

single batch of the drug substance for a period shorter than 3 months but with

more frequent testing than usual. It is considered unnecessary to continue to test a

drug substance through 6 months when a significant change has occurred within

the first 3 months.

2.1.7.3. Drug substances intended for storage in a freezer

Study Storage condition Minimum time period covered

by data at submission

Long term - 20°C ± 5°C 12 months

For drug substances intended for storage in a freezer, the re-test period 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 substances 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.

2.1.7.4. Drug substances intended for storage below -20°C

Drug substances intended for storage below -20°C should be treated on a case-bycase

basis.

2.1.8. Stability Commitment

When available long term stability data on primary batches do not cover the

proposed re-test period granted at the time of approval, a commitment should be

made to continue the stability studies post approval in order to firmly establish the

re-test period.

Where the submission includes long term stability data on three production

batches covering the proposed re-test period, a post approval commitment is

considered unnecessary. Otherwise, one of the following commitments should be

made:

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

production batches, a commitment should be made to continue these studies

through the proposed re-test period.

2. If the submission includes data from stability studies on fewer than three

production batches, a commitment should be made to continue these studies

through the proposed re-test period and to place additional production

batches, to a total of at least three, on long term stability studies through the

proposed re-test period.

3. 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 re-test period.

The stability protocol used for long term studies for the stability commitment

should be the same as that for the primary batches, unless otherwise scientifically

justified.

2.1.9. Evaluation

The purpose of the stability study is to establish, based on testing a minimum of

three batches of the drug substance and evaluating the stability information

(including, as appropriate, results of the physical, chemical, biological, and

microbiological tests), a re-test period applicable to all future batches of the drug

substance manufactured under similar circumstances. The degree of variability of

individual batches affects the confidence that a future production batch will remain

within specification throughout the assigned re-test period.

The data may show so little degradation and so little variability that it is apparent

from looking at the data that the requested re-test period will be granted. Underthese circumstances, it is normally unnecessary to go through the formal statistical

analysis; providing a justification for the omission should be sufficient.

An approach for analyzing the data on a quantitative attribute that is expected to

change with time is to determine the time at which the 95% 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 re-test period

should be based on the minimum time a batch can be expected to remain within

acceptance criteria.

The nature of any 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 of the data on all batches and combined batches (where appropriate) to the

assumed degradation line or curve.

Limited extrapolation of the real time data from the long term storage condition

beyond the observed range to extend the re-test period can be undertaken at

approval time, if justified. This justification should be based on what is known

about the mechanism of degradation, the results of testing under accelerated

conditions, the goodness of fit of any mathematical model, batch size, existence of

supporting stability data, etc. However, this extrapolation assumes that the same

degradation relationship will continue to apply beyond the observed data.

Any evaluation should cover not only the assay, but also the levels of degradation

products and other appropriate attributes.

2.1.10. Statements/Labeling

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 substance. Where applicable, specific instructions

should be provided, particularly for drug substances that cannot tolerate freezing.

Terms such as “ambient conditions” or “room temperature” should be avoided.

A re-test period should be derived from the stability information, and a retest date

should be displayed on the container label if appropriate.