Stability testing of new Drug Products.

Contents

Objective

Scope

Drug Product: General Principles

Selection of Batches

Container Closure System

Specification

Testing Frequency

Storage Conditions

Stability Commitment

Deficiencies

Objective:

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 (Climatic Zones I, II).

Scope:

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.

Drug Product:

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.

Selection of Batches:

At least three primary batches of the drug product.

(Same formulation and in the container closure system as proposed for marketing).

Two batches ----- pilot scale batches (1/10th of production scale or 100,000 tablets or

capsules)

One batch can be smaller.

(where possible different batches of drug substance should be used for manufacturing drug products).

Container Closure System:

Stability testing should be conducted on the dosage form packaged in the container closure

system proposed for marketing (including, as appropriate, any secondary packaging and

container label).

Any available studies carried out on the drug product outside its immediate container or in

other packaging materials can form a useful part of the stress testing of the dosage form or

can be considered as supporting information, respectively.

Specification:

Stability studies should include testing of those attributes of the drug product that are

susceptible to change during storage and likely to influence quality, safety, and efficacy.

The testing should cover, as appropriate, the physical, chemical, biological and microbiological

attributes.

Acceptance criteria for release and shelf life specifications is addressed in ICH Q6A , ICH Q6B

and ICH Q3B for specification of degradation products in drug product.

Shelf life acceptance criteria should be derived from consideration of all available stability

information.

It may be appropriate to have justifiable differences between the shelf life and release

acceptance criteria based on the stability evaluation and the changes observed on storage.

Testing Frequency and Storage Conditions:

For products with a proposed shelf life of at least 12 months

Stability testing Storage Condition Testing frequency

Long term25°C ± 2°C/60% RH ± 5% or

30°C ± 2°C/65% ± 5% RH

Every 3 months over the first year,

Every 6 months over the second year and

Annually thereafter through out the proposed shelf life

Accelerated40°C ± 2°C/75% ± 5% RH

Three time points including initial and final points from a 6

months study (e.g., 0, 3, and 6 months).

Fourth time point or increased testing can be conducted based

on developmental experience where significant changes can

occur.

Intermediate 30°C ± 2°C/65% ± 5% RHA minimum of four time points including initial and final time

points from a 12 month study (e.g., 0, 6, 9 and 12 months).

Reduced designs, i.e., matrixing or bracketing, where the testing frequency is reduced or certain

factor combinations are not tested at all, can be applied, if justified.

A minimum of 12 months long term testing and 6 months accelerated testing data should be

available at the time of submission.

If significant change occurs at any time during accelerated storage condition, intermediate

testing date of minimum 6 months should be included in submission.

Significant Change : In general -

5 % change in assay from initial value.

Any degradation product exceeding its acceptance criteria.

Failure to meet the acceptable criteria for appearance, physical attributes and functionality

test (e.g., hardness).

Failure to meet the acceptable criteria for pH, dissolution for 12 dosage units.

Storage Conditions:

Drug Product in Long Term Intermediate Accelerated

General Case25°C ± 2°C/60% ± 5% RH

or

30°C ± 2°C/65% ± 5% RH

30°C ± 2°C/65% ± 5% RH 40°C ± 2°C/75% ± 5% RH

Semi Permeable Container25°C ± 2°C/40% ± 5% RH

or

30°C ± 2°C/35% ± 5% RH

30°C ± 2°C/35% ± 5% RH40°C ± 2°C / NMT 25%

RH

Refrigerator5°C ± 3°C

NA25°C ± 2°C/60% ± 5% RH

Freezer -20°C ±5°C NA NA

Storage below (- 20°C) Case by case basis.

Impermeable Container Studies can be conducted under any controlled or ambient humidity condition.

Stability Commitment:

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.

If submission includes data of production batches:

At least three production batches, commitment to continue long term studies till proposed

shelf life and accelerated studies for 6 months.

If fewer than three submitted, commitment to study remaining batches to a total of three,

on long term through proposed shelf life and accelerated studies for 6 months.

If no production batches submitted, commitment to place first three production batches

on long term through proposed shelf life and 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.

ANDA Requirement (Can trigger RTR)

The studies should include the stability initiation date along with pull dates to verify the study duration.

6 Months ACC + 6 Months Long term stability data for submission without significant change in results.

2 discrete lots of API should be used for manufacturing the three primary batches

3 Primary batches on marketed pack

(3 Pilot scale batches or 2 Pilot scale batches + 1 small scale)

If a significant change occurs at ACC, then

Intermediate data to be submitted.

Deficiencies:

Stability data do not cover recommended 180 days Submitted data shows only 176 days.

RTR issued

Ex: As per site SOP sample can be with drawn ± X days resulting in 176 days instead of

180 days

Learning: Never remove sample prior to 180 days.

The day product placed in stability chambers is considered as Day 1 in stability studies.

Question and Answers on Stability testing of Drug substances and Products:

Can ANDA be submitted with 6 months ACC and Long term stability data.

FDA Guidance for Industry: Q & A on stability testing (May 2014)

Yes. An applicant should submit 6 months ACC and long term stability data. If any

significant change or failure occurs in acceleration data, the applicant should also

submit 6 months intermediate data at the time of submission.

When do intermediate stability studies need to be initiated in the event of failure at

accelerated condition.

Yes. An applicant should start accelerated, intermediate and long-term stability studies

at the same time so the data are available at the time of submission if the accelerated

stability study fails.

How is the proposed shelf life of supposed to be calculated. Will 6 months of accelerated

data equals 24 months at long term?

Source: FDA Guidance for Industry: Q & A on stability testing (May 2014), GPHA CMC 2016 Workshop.

Data from three submission batches with 6 months ACC and 12 months long term data

and with appropriated post approval stability commitments can be used to support

extrapolation to a 24 months shelf life. (Refer ICH Q1E for detailed calculation)

What is day one in stability studies?

Product manufactured, tested (days 1 through 15), and release COA issued; product

placed in stability ovens on day 21 in the following conditions. (Accelerated, Long-term,

and Intermediate). Day 21 now becomes day 1 for all three conditions.

COA Day 1 in oven

90 days 180 days

Source: FDA Guidance for Industry: Q & A on stability testing (May 2014), GPHA CMC 2016 Workshop.

References

ICH Guidelines - Stability Testing Of New Drug Substances And Products Q1A(R2).

FDA Guidance for Industry, ANDAs: Stability Testing of Drug Substances and Products.

FDA Guidance for Industry, ANDAs: Stability Testing of Drug Substances and Products

– Question and Answers.