What is stability studies
The ability of a pharmaceutical product to retain its physical and chemical properties within specified limits throughout its shelf life.
Types of Stability Studies :
Long term testing
Stability studies under the recommended storage condition for the re-test period or shelf life proposed (or approved) for labeling.
Studies conducted at 30°C/65% RH and designed to moderately increase the rate of chemical degradation or physical changes for a drug substance or drug product intended to be stored long term at 25°C.
Studies designed to increase the rate of chemical degradation or physical change of a drug substance or drug product by using exaggerated storage conditions as part of the formal stability studies. Data from these studies, in addition to long term stability studies, can be used to assess longer term chemical effects at non-accelerated conditions and to evaluate the effect of short term excursions outside the label storage conditions such as might occur during shipping. Results from accelerated testing studies are not always predictive of physical changes.
Climatic zones The four zones in the world that are distinguished by their characteristic prevalent annual climatic conditions.
|Climatic Zone No.||Definition||Storage Condition||Areas covered under the zone|
|I||Temperate climate||21°C & 45% RH.||United Kingdom, Northern Europe, Canada, Russia, United states, Japan etc.|
|II||Subtropical and Mediterranean climate||25°C/60% RH||United States, Japan, Southern Europe (Portugal-Greece) etc.|
|III||Hot & dry climate||30°C/35% RH||Australia, Argentina, Egypt, Iran, Iraq, Sudan, India etc.|
|IVA||Hot & humid climate||30°C/65%||Brazil, Ghana, Indonesia, Nicaragua, Srilanka, Vietnam, Philippines, Uganda, Thailand, India etc.|
|IVB||Hot & very humid climate||30°C/75%||Brazil, Asian countries etc.|
Factors affecting stability of the product
The rate of chemical reaction increases exponentially for each 10°C increase in temperature. This relationship has been observed for nearly all drug hydrolysis and some drug oxidation reaction.
Exposure to primarily, UV illumination may cause oxidation (photo oxidation) and scission (Photolysis) of covalent bonds.
Presence of oxygen, nitrogen.
Esters & beta-lactoms are the chemical bonds that are most likely to hydrolyze in the presence of water.
E.g. the acetyl ester in aspirin is hydrolyzed to acetic acid and salicylic acid in the presence of moisture, but in a dry environment the hydrolysis of aspirin is negligible.
Selection of Batches
For new drug product, samples of at least three consecutive validation batches shall be kept for accelerated, Intermediate and long-term stability.
For routine stability study, one commercial batch shall be kept for long term stability on every year.
Testing frequency shall be determined based on condition at which stability is performed.
Accelerated stability shall be conducted at 0, 3 and 6 months.
Long-term stability studies shall be carried out at the intervals of, Every three months on first year 0, 3, 6,9,12,
Every six months on second year 12, 18, 24
Every year thereafter through the proposed shelf life 24, 36, 48 and 60
Eg: 0, 3,6,9,12,18,24,36,48 and 60 months.
Intermediate Intermediate stability studies (minimum four time points, including initial and final points) shall be carried out at 0,3,6,9 and 12 months or up to 60 months.
Sampling for Stability Study
QA shall inform to QC regarding type of stability study to be performed. QC shall calculate the sample quantity and shall inform to QA.
Total sample quantity per batch shall be equivalent to 1.5 times of the quantity required for single complete or partial analysis & based on number of stations plus additional one station (since stability testing has to be continued for 12 month beyond the expiry).
Incubation of Stability Samples and Storage conditions
Samples shall be incubated as per below guideline.
Identify the storage conditions based on the Pharmacopoeial data or literature information or R&D information. For add on batch use long term storage conditions.
The long term testing shall cover a minimum of 12 months’ duration on at least three validation batches at the time of submission and shall be continued for a period of time sufficient to cover the proposed shelf life.
Long term, accelerated, and, where appropriate, intermediate storage conditions for drug products are detailed in the sections below.
|Study||Storage condition||Minimum time period covered by data at submission|
|Long term||25°C ± 2°C / 60% RH ± 5% RH or 30°C ± 2°C / 65% RH ± 5% RH||12 months|
|Intermediate*||30°C ± 2°C / 65% RH ± 5% RH||6 months|
|Accelerated||40°C ± 2°C / 75% RH ± 5% RH||6 months|
* 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.
The initial application should include a minimum of 6 months’ data from a 12-month study at the intermediate storage condition. Temperature & Humidity of stability incubator shall be monitored on daily basis. If incubation of the stability samples is delayed by 30 days or more from the release date of the batch, initial (0 month) analysis shall be performed again before incubation.
Analysis of the sample shall be performed on the due date or if not possible, then complete within below tolerance limit from due date.
|Sr. No.||Stability Station||Tolerance (From due date of analysis)|
|1.||1M , 2M, 3M Accelerated, 3M long term, 3M Intermediate term||± 07 days|
|2.||6M Accelerated 6M, 9M, 12M long term. 6M, 9M, 12M Intermediate term.||± 15 days|
|3.||18M & onwards of long term.||± 30 days|
If there is any out of trend result or failure to meet specification (significant change) in stability analysis, results shall be intimated to Head – QC.
Head – QC or designee shall investigate the out of trend (OOT) results according to the OOT SOP .
In case of Changes in the manufacturing process or site:
If minor changes done in the manufacturing process, Sample from batches produced under each change shall be added to stability program (one batch).
If major changes done in the manufacturing process, collect the samples from the new batches (three batches) and perform the stability like new product. In such a case the protocol and report procedure number shall be changed.
In case of manufacturing site change, evaluate the affect on stability of the drug product by keeping one batch for stability.
Stability guideline :
ICH guideline: ICH Q1A (R2)