Download - Stabilty study ppt
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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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