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ICH Guidelines for Stability Studies

Guided by: Presented by: Dr. Arpana Patil Salim Mulla (M.Pharm, Phd) M.Pharm (SEM-I ) Alard College of Pharmacy

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Drug stability refers to the capacity of a drug substance or

product to remain within established specifications of identity,

strength, quality, and purity in a specified period of time.

Stability is officially defined as the time during which the drug

product retains the same properties and characteristics that it

possessed at the time of manufacture.

Drug stability definition

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STAGE 1- Early stage stress and accelerated testing with drug

substances

STAGE 2- Stability on pre-formulation batches

STAGE 3- Stress testing on scale-up batches

STAGE 4- Accelerated and long term testing for registeration

purposes

STAGE 5- On-going stability testing

STAGE 6- Follow-up Stabilities

Stability studies are incorporated at all stages of drug product life cycle from early stages of product development to late stage follow-up stabilities. In particular the life cycle can be segregated into 6 different stages

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To gather information during pre-formulation stage to

produce a stable product

To determine maximum expiration date.

To get an idea of storage condition.

To determine the packaging components.

To establish retest period of pharmaceuticals.

To establish transport condition.

OBJECTVES OF STABILITY SYUDY

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Chemical degradation of active drug may reduce the quality of therapeutic indices like 5- flurouracil, carbamazepine etc have very small therapeutic range, sight degradation of drug may produce sub therapeutic concentration.

After degradation a drug may produce more toxic product(s) which may be more toxic than the parent product.

Instability of drug product reduce bioavailability. This may be caused by physical or chemical instability.

Instability of a product may change the physical appearance of the product.

APPLICATION OF STABILITY STUDIES IN PHARMACEUTICALS

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The ICH (International Conference on Harmonization)

Guidelines Q1A(R2) “Stability testing of new drug

substances and products” is the “gold standard” for

conducting stability studies. This is valid for “new drug

substances or drug products” that are sufficient for a

registration application.

Regulations and Guidances

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Q1A- Stability testing of new Drug Substances and Products

Q1B- Stability Testing : Photostability Testing of New Drug Substances and products

Q1C- Stability Testing for new Dosage forms Q1D- Bracketing and Matrixing Designs for Stability

Testing of New Drug Substsances and products Q1E- Evaluation of stability data Q1F- Stability data package for registration

ICH GUIDELINES FOR STABILITY STUDIES

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OBJECTIVE OF THE GUIDELINE:

It defines stability of drug substances and drug

product for registration of application of associated

drug, within three regions of ICH i.e. EU, Japan, USA.

ICH guideline Q1-A (stability studies)

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1. Purpose of stability testing is to provide evidence how quality varies with time under influences of temperature humidity light

2. Establish re-test period for drug substancesRE-TEST PERIOD:

The period after which samples of the drug substances should be examined to ensure that the material is still in compliance with the specification, and thus suitable for use in manufacturing. A retest period should be proposed on the basis of stability results and may be extended to five years (e.g. Ethambutol 2HCI, or isoniazid)

PRINCIPLES OF THE GUIDELINES

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3. Establish shelf life for drug products:• SHELF LIFE (EXPIRY DATE/EXPIRATION DATING PERIOD):

The period of time during which a pharmaceutical product, if stored correctly, is expected to comply with the specification as determined by stability studies on a number or batches of the product.

The shelf life is used to establish the expiry date of DRUG PRODUCT.

4. Recommends storage conditions5. Gives Test conditions based on analysis of effects of climatic conditions in the three regions of the EU, japan, USA.

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Stress testing:

These guidelines help to identify the likely degreadation

products, to establish the degradation pathway of the

molecule.

Selection of batches:

At least 3 primary batches of the drug substances should

be selected. The quality should be representative to

quality of material used for production scale.

Stability testing protocol

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Container Closure system:

◦ Should simulate packaging proposed for storage and distribution.

Specification:

◦ List of tests,

◦ Reference to analytical procedure,

◦ Proposed acceptance criteria

◦ Test Attributes

◦ Attributes that are susceptible to changed storage,

◦ Influence quality, safety and/or efficacy

◦ Should cover physical, chemical, biological and microbiological

attributes.

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Testing frequency:

Testing frequency for products proposed shelf life of at least 12

months.

FIRST YEAR…. 3 month

SECOND …… 6 month

Thereafter…. Annually through out the proposed retest period .

At accelerated storage condition:

Minimum three time points (0,3 and 6 months)from a 6 month study

At intermediate storage condition:

Minimum of four time points (0,6,9 and 12 months) from a 12 month

study.

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Long term testing should cover a minimum of 12 months duration on at least three primary bacterial batches at time of submission and should be continue sufficient to covered the proposed retest period.

General

STORAGE CONDITIONS

Study Storage condition DurationLong term 25o C ± 2o C/60%

±5% Or

30oC ± 2oC/65% ± 5%

12 months

Intermediate

30oC ± 2oC/65% ± 5%

6 months

Accelerated

40oC ± 2oC/75% ± 5%

6 months

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Drugs packed in semi permeable membrane

containers:Study Storage Condition Duration

Long term 25oC ± 2oC/ 40% RH ± 5%Or

30oC ± 2oC/ 35% RH ± 5%

12 months

Intermediate 30oC ± 2oC/ 65% RH ± 5% 6 months

Accelerated 40oC ± 2oC/ 75% RH ± 5% 6 months

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Drug substance intended for storage in a refrigerator

If significant change between 3 and 6 month at accelerated testing propose re-test data based on real time data. (LONG TERM STUDY)

If significant change within 3 month discussion should address excursion outside label storage. Single batch shorter than 3 months with more frequent testing

Study Storage condition Duration

Long term 5oC ± 3oC 12 months

Accelerated 25oC ± 2oC/60%± 5% 6 months

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Drug substance intended for storage in a freezer

Re-test period based on real time data at long term storage condition.

In absence of accelerated storage condition testing on a single batch at an elevated temperature e.g. 5oC 3oC address short term excursions

Study Storage condition

Duration

Long term -20oC ± 5oC 12 month

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Stability commitment: When retest period not covered or not mentioned. Long term stability data do not cover proposed retest period

granted at time of approval to establish re test period. Not required for submission which includes data from 3

production batches commitment to continue through proposed retest period

Fewer than three production batches commitment continue through proposed retest period and place additional production batches to a total of three on long term stability through proposed retest period.

No production batches commitment to place first three production batches on long term stability studies through proposed retest period.

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Evaluation: A systematic approach should be adopted in the

presentation and evaluation of the stability information which covers the physical, chemical & biological parameter.

A minimum of 3 batches of drug product was tested.

The analyst must found the batch to batch variability and

if it is small than only it is accepted and it can be done by

different statistical tests. Where the data shows so little degradation and so little

variability that is apparent from looking the data that the requestedshelf life will be granted. It is normally unnecessary to go through the formal statistical analysis.

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Significant change of drug substance or product:

A 5% change in assay from its initial value. Any degradation product exceeding its acceptance

criterion. Failure to meet the acceptance criteria for apperance,

physical attributes and functionality test (e.g. colour, phase separation, hardness).

As appropriate for the dosage form, e.g. failure to meet the acceptance criteria for dissolution for 12 dosage units.

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Statements/Labelling: A storage statement should be established based on the

stability evaluation of the drug substances.

Terms such as “ambient conditions” or “room

temperature” should be avoided.

Retest date should be displayed on the container label

if appropriate.

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References: www.ich.org/product/guidelines/quality.html

www.ema.europa.eu/pdfs/human/ich/273699en.pdf

www.ich.org/fileadmin

/.../ICH.../Guidelines/.../Q1BGuideline.pdf

Apps.who.int/prequal/traninresources/pq…/

stabilitystudies.ppt

Drug Stability: Principles and Practices. By Jens T. Carstensen. Marcel Dekker: New York, 1990, CRC press publication, Third edition, pg no. 54-110.

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