SOP FOR ACCELERATED STABILITY AND SHELF-LIFE CALCULATION

PURPOSE: To lay down a method for accelerated stability and to find out the shelf life of the product for Cephalosporin Block.

SCOPE: This SOP is applicable for the standard operating procedure pertaining to all departments.

RESPONSIBILITY

Preparation of SOPs: Officer/ Executive of Concerned Departments

Checking and Review of the SOPs: Next Level of the Concerned Department

Approval of the SOPs: Head of Concerned Department

Authorizing of SOP: Head QA/ His or her Designee

ACCOUNTABILITY: The accountability of implementation and ensuring compliance of the SOP lies with head of respective Department.

PROCEDURE:

Definition:

Stability: Stability is officially defined as the time lapse (period) during which drug substance (API) or drug product (FPP) to retains the same properties and characteristics(i.e. Physical, Chemical, Microbiological, Therapeutic and Toxicological specifications to maintain its identity, strength, quality, and purity ) that it possessed at the time of manufacture.

Types of Stability:

• Chemical
• Physical.
• Genotoxic.
• Therapeutic.
• Microbiological

 

Type of Stability	Condition Maintained throughout the shelf life of drug product
Chemical	Each active ingredient retains its chemical integrity and labeled potency within the specified limit
Physical	The original Physical properties including appearance palatability, uniformity, dissolution and suspendability are retained.
Microbiological	Sterility or resistance to microbial growth is retained according to specified requirement.
Therapeutic	Therapeutic effect remains unchanged
Toxicological	No significant increase in toxicity occurs

 

Types of stability studies

• Accelerated stability testing
• Intermediate testing
• Long term testing
• Stress testing
• Forced degradation testing
• Photo stability testing
• Thermal analytical techniques for stability testing (DSC, microcalorimetry).

ACCELERATED STABILITY STUDIES

Accelerated Stability Studies is to predict the shelf life of the product, by accelerating the rate of decomposition, preferably by increasing the temperature of reaction conditions.

All medicinal products decompose with time. Paradoxically, when this decomposition is being assessed the skilled formulator becomes a victim of his own expertise, as a good formulation will take a long time to decompose. When the perceived optimal formulation is decided, attempts can be made to predict its likely stability at proposed storage conditions. These may be at 25℃ for ambient room temperature (or 30℃ for use in hot climates), or 0-40℃ for a refrigerator.

Instability in modern formulations is often detectable only after considerable storage periods under normal conditions.

To assess the stability of a formulated product it is usual to expose it to “high stress”, i.e. condition of temperature, humidity and light intensity that cause break down.

High stress conditions enhance the deterioration of the product and so reduce the time required for testing.

Therefore, studies are designed to increase the rate of chemical degradation and physical change of a drug by using exaggerated storage conditions as part of the formal stability testing programmed.

This enables more data to be gathered in shorter time, which in turn will allow unsatisfactory formulation to be eliminated early in a study and will also reduce the time for a successful product to reach a market.

It must be emphasized that extrapolation to normal storage condition must be made with care, the formulator must be sure that such extrapolation is valid.

The results of accelerated testing studies are not always predictive of physical changes.

The amount of decomposition that is acceptable in fixing an expiry date depends on the particular drug. This will be small if therapeutic index is low or if the decomposition products are toxic.

Testing Frequency :

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.

Accelerated stability study Storage condition

Storage Condition	Testing Condition
Controlled room temperature 20℃- 25℃	40℃ and 75% RH for 6 months
Refrigerated condition 2℃- 8℃	25℃ and 60% RH for 6 months
Freezer condition – 2℃-to -10℃	5℃ for 6 months

 

Significant change at accelerated condition:

If significant change occurs within the first 3 months’ testing at the accelerated storage condition, the proposed retest period or shelf life should be based on long-term data. 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.

No Significant change at accelerated condition:

Where no significant change occurs at the accelerated condition, the retest period or shelf life would depend on the nature of the long-term and accelerated data. The decision tree in Flowchart A can be used as an aid.

LONG-TERM STABILITY and INTERMEDIATE STABILITY STUDIES

Definition:

Experiments on the physical, chemical, biological, biopharmaceutical and microbiological characteristics of an API or FPP, during and beyond the expected shelf-life and storage periods of samples under the storage conditions expected in the intended market. The results are used to establish the re-test period or the shelf-life, to confirm the projected retest period and shelf-life, and to recommend storage conditions.

Intermediate stability 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. The intermediate storage condition has been changed between different temperature and relative humidity conditions in the following sections:

Storage condition :

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.

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

 

It can 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.

In general, “significant change” for a drug product is defined as:

A 5% change in assay from its initial value; or failure to meet the acceptance criteria for potency when using biological or immunological procedures

Any degradation product’s exceeding its acceptance criterion, Failure to meet the acceptance criteria for appearance, physical attributes, and functionality test (e.g., color, phase separation, re-suspendibility, caking, hardness, dose delivery per actuation).

However, some changes in physical attributes (e.g., softening of suppositories, melting of creams) may be expected under accelerated conditions

As appropriate for the dosage form:

Failure to meet the acceptance criterion for pH.

Failure to meet the acceptance criteria for dissolution for 12 dosage units.

Drug products intended for storage in a refrigerator 

If the drug product is packaged in a semi-permeable container, appropriate information should be provided to assess the extent of water loss. 

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 shelf life should be based on the real time data available from 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 shipment and handling. 

This discussion can be supported, if appropriate, by further testing on a single batch of the drug product for a period shorter than 3 months but with more frequent testing than usual. 

It is considered unnecessary to continue to test a product through 6 months when a significant change has occurred within the first 3 months

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

No significant change at intermediate condition: If there is no significant change at the intermediate condition, extrapolation beyond the period covered by long-term data can be proposed; however, the extent of extrapolation would depend on whether long-term data for the attribute are amenable to statistical analysis.

Data not amenable to statistical analysis: When the long-term data for an attribute are not amenable to statistical analysis, the proposed retest period or shelf life can be up to 3 months beyond the period covered by long-term data, if backed by relevant supporting data.

Data amenable to statistical analysis: When the long-term data for an attribute are amenable to statistical analysis, but no analysis is performed, the extent of extrapolation should be the same as when data are not amenable to statistical analysis. However, if a statistical analysis is performed, the proposed retest period or shelf life can be up to one-and-half times, but should not be more than 6 months beyond, the period covered by long-term data, when backed by statistical analysis and relevant supporting data.

Significant change at intermediate condition: Where significant change occurs at the intermediate condition, the proposed retest period or shelf life should not exceed the period covered by long-term data. In addition, a retest period or shelf life shorter than the period covered by long-term data could be called for.

STABILITY STUDY UNDER STRESS TESTING: Stress testing of the drug substance can help identify the likely degradation products, which can in turn help to 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.

Photo stability testing should be an integral part of stress testing.

Perform essentially during Preformulating study. Done on single batch same composition & quality as marketing batch including packaging. Conducted for period of 6 months. 

Stress testing of FPPs in solid state:

STORAGE CONDITION	TESTING time period
40°C & 75% RH open storage	3 months
50°Cto 60°C , ambient RH open storage	3 months

Stress testing of API in solution

STORAGE CONDITION	TESTING time period
pH   ± 2, room temperature	2 weeks
pH   ± 7, room temperature	2 weeks
pH   ± 10-12, room temperature	2 weeks
H2O2 , 0.1-2 % at neutral pH, room temperature	24 hours

TESTING FREQUENCY

STABILITY TESTING	TESTING INTERVAL
Real time testing	0,3,6,9,12,15,24 months
Accelerated testing	0, 3 & 6 months
Intermediate	0,6,9 & 12 months

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.

If the submission includes data from stability studies on at least three production batches, a commitment should be made to continue the long-term studies through the proposed shelf life and the accelerated studies for 6 months.

If the submission includes data from stability studies on fewer than three production batches, a commitment should be made to continue the long term studies through the proposed shelf life and the accelerated studies for 6 months, and to place additional production batches, to a total of at least three, on long term stability studies through the proposed shelf life and on accelerated studies for 6 months.

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 shelf life and on 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. Where intermediate testing is called for by a significant change at the accelerated storage condition for the primary batches, testing on the commitment batches can be conducted at either the intermediate or the accelerated storage condition.

However, if significant change occurs at the accelerated storage condition on the commitment batches, testing at the intermediate storage condition should also be conducted.

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 product.

Where applicable, specific instruction should be provided, particularly for drug products that cannot tolerate freezing. Terms such as “ambient conditions” or “room temperature” should be avoided.

There should be a direct link between the label storage statement and the demonstrated stability of the drug product. An expiration date should be displayed on the container label.

 A Decision Tree for Data Evaluation for Retest Period or Shelf-Life Estimation for Drug Substances    or Products (excluding Frozen Products): 

Prediction of shelf life from accelerated stability data:

Based on the principle of chemical kinetics demonstrated by

Garret and Carper method.

Free and Blythe method

Shelf-Life Determination Based on Arrhenius Plot (Garret and Carper method)

The mathematical prediction of shelf life is based on the application of the arrhenious equation, which indicates the effect of temperature on the rate constant, k, of a chemical reaction of thermodynamic temperature, 1/T, is a straight line.

v  If the slope of this line is determined from the results of temperature by extrapolation, the k value obtained. And this k value is substituted in appropriate order of reaction allows the amount of decomposition after a given time. Preliminary experiments are there for necessary to determine this order.

K=Ae-Ea/RT Log K=Log A – Ea/2.303*RT

Where, K= rate constant

R= gas constant =1.987 cal/mole

T = absolute temperature

A = frequency factor

Ea = energy of activation T

10% = (2.303/K) *(log100/90)

T90% = (2.303/K) *(log100/10)

Garret and Carper method: Keep several samples of the drug product at least three temperatures, such as 40℃, 50℃ and 60℃.

Determine the drug content at all three storage points by taking a number of samples and take the mean drug content. We do this for a few weeks.

At each temperature we plot a graph between time and log percent drug remaining. If the decomposition is first order this gives a straight line. If it is zero order, percent drug remaining versus time will give a straight line.

Next, we take the log K or log of reaction constant on Y axis and 1/T x 10-3 on X axis and draw a best fit line. This line is the Arrhenius Plot, extrapolate this line to get k at 25℃ and from this we calculate the shelf-life.

If the reaction is following zero-order

Expiration date at 25 o C = Initial potency – minimum potency / reaction rate at 25 °C tx =Yo – Yx/ Ko

If the reaction is following first order

Expiration date at 25 o C (tx) = Log initial potency – log minimum potency/reaction rate at 25

tx =log Yo – log Yx / K1

Where

Yo = initial potency

Yx = final potency

Ko = zero order constant

K1 = first order constant

 SHELF-LIFE DETERMINATION Based on t90 values (Free and Blythe /method)

In this method the fraction life period is plotted against a reciprocal temperature and the time in days required for drug to decompose to some fraction of its original potency at room temp.

This approach clearly illustrates in below fig. the log% of drug remaining is plotted against time and days and the time for the loss line at several temp. to reach 90% of the theoretical potency is noted by the dotted line.

Shelf life and expiration date are estimated in this way. The log time to 90% is then plotted against 1/T and the time for 10% loss of potency at room temperature can be obtain from the resulting straight line by extrapolation to 25 C. 

SHELF-LIFE DETERMINATION BASED ON REAL TIME TESTING: Another method which involves real time testing and statistical analysis, followed for determining shelf life.

Keep three batches for stability study at least for 1 year at one fixed temperature. Test them at 0, 1, 3, 6, 9, and 12 months for drug content. At each testing time test a number of samples, so that you have a mean and a standard deviation value of the result.

Now plot the graph of % drug content on Y axis and time on X axis along with confidence intervals. Where the lower 95% confidence curve intersects minimum potency, there you fix the shelf life.

 REFERENCE:

SOP FOR SOP

Guidelines: ICH Q1 AR AND Q1 (E)