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STABILITY TESTING OF NEW DRUG SUBSTANCES Q1A(R2)

STABILITY TESTING OF NEW DRUG SUBSTANCES  Q1A(R2)

COVER NOTE FOR REVISION OF Q1A(R)

The changes made in Q1A(R) that result from adoption of ICH Q1F “Stability Data Package for Registration Applications in Climatic Zones III and IV”. These changes are:

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:

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

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:

  • Drug products packaged in semi-permeable containers

Mid-stream 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.

TABLE OF CONTENTS
INTRODUCTION
Objectives of the Guideline
Scope of the Guideline
General Principles
GUIDELINES
Drug Substance
General
Stress Testing
Selection of Batches
Container Closure System
Specification
Testing Frequency
Storage Conditions
Stability Commitment
Evaluation
Statements/Labeling

STABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS
INTRODUCTION
Objectives of the Guideline
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 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.

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.

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.

GUIDELINES
Drug Substance
General
Information on the stability of the drug substance is an integral part of the systematic approach to stability evaluation.

Stress Testing
Stress testing of the drug substance is to 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.

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.

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.

Specification
Specification,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.

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.

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.

Storage Conditions
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.

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
or
30°C ± 2°C/65% RH ± 5% RH

Intermediate**    30°C ± 2°C/65% RH ± 5% RH                                             6 months
Accelerated           40°C ± 2°C/75% RH ± 5% RH                                             6 months

*It is up to the applicant to decide whether long term stability studies are performed at 25 ± 2°C/60% ,RH 5% RH or 30°C ± 2°C/65% RH 5% RH.

**If 30°C ± 2°C/65% RH 5% RH is the long-term condition, there is no intermediate condition.

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.

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.

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.

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.

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

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 retest 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.

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.

Under these 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.

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.

Referances :ICH HARMONISED TRIPARTITE GUIDELINE -STABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS Q1A(R2) .

About Pharmaceutical Guidanace

Mr. Shiv Kumar is the Author and founder of pharmaceutical guidance, he is a pharmaceutical Professional from India having more than 14 years of rich experience in pharmaceutical field. During his career, he work in quality assurance department with multinational company’s i.e Zydus Cadila Ltd, Unichem Laboratories Ltd, Indoco remedies Ltd, Panacea Biotec Ltd, Nectar life Science Ltd. During his experience, he face may regulatory Audit i.e. USFDA, MHRA, ANVISA, MCC, TGA, EU –GMP, WHO –Geneva, ISO 9001-2008 and many ROW Regularities Audit i.e.Uganda,Kenya, Tanzania, Zimbabwe. He is currently leading a regulatory pharmaceutical company as a head Quality. You can join him by Email, Facebook, Google+, Twitter and YouTube

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