stability studies
TRANSCRIPT
Many factors affect the stability of the pharmaceutical product
including the stability of the active ingredient's. The potential
interaction between active ingredients, the manufacturing
process, the dosage form, the container and closer, storage. The
environmental conditions encounter during transport, storage,
handling and length of times, between manufacture and use.
The purpose of the stability study testing is to prove on how the
quality of a drug substance or the drug product varies with time,
under the influence of variety of environmental factors such as
temperature, humidity and light.
Many factors affect the stability of the pharmaceutical product
including the stability of the active ingredient's. The potential
interaction between active ingredients, the manufacturing
process, the dosage form, the container and closer, storage. The
environmental conditions encounter during transport, storage,
handling and length of times, between manufacture and use.
The purpose of the stability study testing is to prove on how the
quality of a drug substance or the drug product varies with time,
under the influence of variety of environmental factors such as
temperature, humidity and light.
The mean kinetic temperature in any part of theworld can be derived from climatic data and worldcan be divided into four climatic zones (I-IV).
The stability information generated in any one of thethree regions i.e. Japan, U.S and E.C would bemutually, acceptable to the other two regions.
Information on the stability of the drug product is anintegral part of the systematic approach to stabilityevaluation.
Interpretation of data is critical in stability studies. Itcomes with experience and is important inestablishing “OOT” (out of trend) results. OOTmeans abnormal fluctuations in the test results,which are not acceptable.
The mean kinetic temperature in any part of theworld can be derived from climatic data and worldcan be divided into four climatic zones (I-IV).
The stability information generated in any one of thethree regions i.e. Japan, U.S and E.C would bemutually, acceptable to the other two regions.
Information on the stability of the drug product is anintegral part of the systematic approach to stabilityevaluation.
Interpretation of data is critical in stability studies. Itcomes with experience and is important inestablishing “OOT” (out of trend) results. OOTmeans abnormal fluctuations in the test results,which are not acceptable.
The stability studies are separated into
1.Chemical
2.Biochemical
3.Physical stability
Physical factors such as heat,light, and moisturemay initiate or accelerate the chemical reactions.So chemical compound, physical dimensions areincluded in stability studies. Physical and chemicalstability will be discussed to predict shelf life.
The stability studies are separated into
1.Chemical
2.Biochemical
3.Physical stability
Physical factors such as heat,light, and moisturemay initiate or accelerate the chemical reactions.So chemical compound, physical dimensions areincluded in stability studies. Physical and chemicalstability will be discussed to predict shelf life.
1.Incompatibility
2.Oxidation-reduction
3.Hydrolysis
4.Decorboxilation
5.Racemization
6.Photochemical
7.Ionisation radiation
Stability studies include statisticalevaluation of stability data, determination of shelf-life or expiration date and informing the storageconditions of a drug product and raw materials.
1.Incompatibility
2.Oxidation-reduction
3.Hydrolysis
4.Decorboxilation
5.Racemization
6.Photochemical
7.Ionisation radiation
Stability studies include statisticalevaluation of stability data, determination of shelf-life or expiration date and informing the storageconditions of a drug product and raw materials.
Stability studies should be conducted to evaluate
1.New procedures or new manufacturing process.
2.REprocess / rework batches.
3.Batches where change control effected.
4.Existing commercial batches evaluation.
5.Validated batches for filing.
Stability Category should be of there types:
1.Accelerated-A
2.Intermediate-M
3.Long term-L
Stability studies should be conducted to evaluate
1.New procedures or new manufacturing process.
2.REprocess / rework batches.
3.Batches where change control effected.
4.Existing commercial batches evaluation.
5.Validated batches for filing.
Stability Category should be of there types:
1.Accelerated-A
2.Intermediate-M
3.Long term-L
Procedure for stability study:After collecting the samples for stability study
prepare the stability study schedule as for thefollowing stability study schedule Tracker.
B.No
Loaded date
ACC/LT/INT
Initial
Test stations in months1 2 3 6 9 1
218
24 36 48
B.No
Loaded date
ACC/LT/INT
Initial 1 2 3 6 9 1
218
24 36 48
Storage ConditionsI. For products storage conditions labeled as store at 25%
Temp.˚c Humidity % periodLong term (L) 25 2 or30 2 60 5 or 65 5 12monthsAccelerated (A) 40 2 75 5 6monthsIntermediate (M) 30 2 65 5 6months
II. For products storage conditions labeled as store at 8 c to15 c.
Temp. c Humidity%Long term (L) 15 2 ---------Accelerated (A) 30 2 65 5
Storage ConditionsI. For products storage conditions labeled as store at 25%
Temp.˚c Humidity % periodLong term (L) 25±2 or30±2 60±5 or 65±5 12monthsAccelerated (A) 40±2 75±5 6monthsIntermediate (M) 30±2 65±5 6months
II. For products storage conditions labeled as store at 8°c to15°c.
Temp.°c Humidity%Long term (L) 15±2 ---------Accelerated (A) 30±2 65±5
III. For products storage conditions labeled as store inrefrigerator 2 c to 8 c.
Temp. c Humidity%Long term (L) 5 3 -------
Accelerated (A) 25 2 60 5
Other accelerated temperature and humidity. As perthe requirement of the regulatory bodies.
The number of samples to be taken depends upon thenumber of stations 3months, 6months, 9months and1 year.
III. For products storage conditions labeled as store inrefrigerator 2°c to 8°c.
Temp.°c Humidity%Long term (L) 5±3 -------
Accelerated (A) 25±2 60±5
Other accelerated temperature and humidity. As perthe requirement of the regulatory bodies.
The number of samples to be taken depends upon thenumber of stations 3months, 6months, 9months and1 year.
Stability samples should be stored in containers that simulate
the market containers.
Example: If the product is packed in bags within fiber drums for
marketing, Stability samples can be packed in the same containers.
Separate sample pack should be prepared for each station of testing
for microbial test. Collect additional quantity of sample to conduct
two complete tests. Sample pack should be labeled as for SOP.
Normally first 3 production batches should be place on the stability
monitoring program to conform the expire date, how ever if data
from previous studies shows that the product is expected to remain
stable for at least for two years, fewer than 3 can be used.
Stability samples should be stored in containers that simulate
the market containers.
Example: If the product is packed in bags within fiber drums for
marketing, Stability samples can be packed in the same containers.
Separate sample pack should be prepared for each station of testing
for microbial test. Collect additional quantity of sample to conduct
two complete tests. Sample pack should be labeled as for SOP.
Normally first 3 production batches should be place on the stability
monitoring program to conform the expire date, how ever if data
from previous studies shows that the product is expected to remain
stable for at least for two years, fewer than 3 can be used.
After that at least one batch per year manufacturedshould be added to the stability-monitoring programand tested annually to conform the stability.
If the products are with short shelf-life testingshould be done more frequently.
Example: bio-technological, biological and otherproducts with shelf-life of one year or less should betested monthly for the first three months and at threemonths interval afterwards. If data available at ninemonths interval can be consider. Should not test theretention/reserved samples for stability studies theyare meant for the evaluation of a quantity of theproduct.
After that at least one batch per year manufacturedshould be added to the stability-monitoring programand tested annually to conform the stability.
If the products are with short shelf-life testingshould be done more frequently.
Example: bio-technological, biological and otherproducts with shelf-life of one year or less should betested monthly for the first three months and at threemonths interval afterwards. If data available at ninemonths interval can be consider. Should not test theretention/reserved samples for stability studies theyare meant for the evaluation of a quantity of theproduct.
Analysis of stability samplesA documented on going program should be designed
to monitor the stability characters of the productand the results should be used to confirm thestorage conditions and expiry date or retest date.
1.Stability samples should be kept in the chamberswith in 15 days after the batch release.
2.If delayed for more than 15 days sample should bere-analysed for initial results.
3.The release / re-test results should be used as initial
Data for test parameters.
Analysis of stability samplesA documented on going program should be designed
to monitor the stability characters of the productand the results should be used to confirm thestorage conditions and expiry date or retest date.
1.Stability samples should be kept in the chamberswith in 15 days after the batch release.
2.If delayed for more than 15 days sample should bere-analysed for initial results.
3.The release / re-test results should be used as initial
Data for test parameters.
4.Keep samples in the respective environmentchamber and record the IN-OUT of stability samplesin environmental chamber (Stability chamber) Logbook.
5.After with drawl of sample form stability chambers,the sample should be taken for analysis with in5days of the schedule. If it is delayed the sampleshould be kept in the refrigerator.
6.The refrigerator samples should be analysed with in15days.
7.Incase of any deviation take approval of QA andplan the activity accordingly. Investigate as forOOT-SOP.
4.Keep samples in the respective environmentchamber and record the IN-OUT of stability samplesin environmental chamber (Stability chamber) Logbook.
5.After with drawl of sample form stability chambers,the sample should be taken for analysis with in5days of the schedule. If it is delayed the sampleshould be kept in the refrigerator.
6.The refrigerator samples should be analysed with in15days.
7.Incase of any deviation take approval of QA andplan the activity accordingly. Investigate as forOOT-SOP.
8.Record the analytical findings in approved analyticalprotocol and maintained all raw data along with datasheet.
9.Summarize the stability protocol and prepare thefinal stability report.
10.If any failure observed during stability studiesinvestigation should be carried out on analyticalparameters only.
Before reporting the results compare the test resultsfor the present test station with that of the previoustest station or with that of the other stations. Trendshould be checked with the report, which determinethe percent of fluctuations of the range.
8.Record the analytical findings in approved analyticalprotocol and maintained all raw data along with datasheet.
9.Summarize the stability protocol and prepare thefinal stability report.
10.If any failure observed during stability studiesinvestigation should be carried out on analyticalparameters only.
Before reporting the results compare the test resultsfor the present test station with that of the previoustest station or with that of the other stations. Trendshould be checked with the report, which determinethe percent of fluctuations of the range.
Abnormal Ranges
When significant change occurs during storage underaccelerated condition, Discontinue the accelerated study andcontinue for intermediate or long term storage conditions.Significant change for a drug product is defined as follows.
1. A 5% change in Assay from initial value or failure to meetthe acceptance criteria for potency.
2. Failure to meet the acceptance criteria for appearance(color), physical attributes and functionality test.
3. Failure to meet acceptance criteria for PH.
The following values are considered for the molecules,which does not show a degradative trend, based on theprevious data available.
Abnormal Ranges
When significant change occurs during storage underaccelerated condition, Discontinue the accelerated study andcontinue for intermediate or long term storage conditions.Significant change for a drug product is defined as follows.
1. A 5% change in Assay from initial value or failure to meetthe acceptance criteria for potency.
2. Failure to meet the acceptance criteria for appearance(color), physical attributes and functionality test.
3. Failure to meet acceptance criteria for PH.
The following values are considered for the molecules,which does not show a degradative trend, based on theprevious data available.
1. Water content or LOD:Ex:<1% --- 20%
Ex: 1% --- 20%
Ex: >2% --- 10%
2. Specific optical rotations(SOR):Form 0 to 25 --- 1
Form 25 to60 --- 2
Form 60 and above---3
3. Color absorbance:Increase in colour more than 0.15AU.
1. Water content or LOD:Ex:<1% --- 20%
Ex: 1% --- 20%
Ex: >2% --- 10%
2. Specific optical rotations(SOR):Form 0° to 25° --- 1°Form 25°to60° --- 2°Form 60° and above---3°
3. Color absorbance:Increase in colour more than 0.15AU.
4. Related substances:Some degradable impurities may come more thanthe expected % then look for the accelerated dataand the extent of degradation of that impurity up to6 M station.
5. Assay: Variation may be more than 1% for rawmaterials and intermediates, variation is more than3% for formulations and for dissolution tests thevariation is more than 5%.
4. Related substances:Some degradable impurities may come more thanthe expected % then look for the accelerated dataand the extent of degradation of that impurity up to6 M station.
5. Assay: Variation may be more than 1% for rawmaterials and intermediates, variation is more than3% for formulations and for dissolution tests thevariation is more than 5%.
How to avoid Abnormalities
To avoid the abnormalities in the stability studies, STP’s,specifications and available literature to be studied beforestarting a stability studies project, go through the previoustest station values. Initial values or the available stabilityreport.
Example: Some sample may be hygroscopic in naturenecessary precaution to be taken while handling thesematerials. i.e direct weighing of the sample in the container.In colour absorbance dilution to be made and colour valuesto be taken immediately. Accurate dilutions are necessary toavoid colour variations.For specific optical rotation (SOR) experiments temperatureof the sample solution is important
How to avoid Abnormalities
To avoid the abnormalities in the stability studies, STP’s,specifications and available literature to be studied beforestarting a stability studies project, go through the previoustest station values. Initial values or the available stabilityreport.
Example: Some sample may be hygroscopic in naturenecessary precaution to be taken while handling thesematerials. i.e direct weighing of the sample in the container.In colour absorbance dilution to be made and colour valuesto be taken immediately. Accurate dilutions are necessary toavoid colour variations.For specific optical rotation (SOR) experiments temperatureof the sample solution is important
So maintain the given temperature accurately.Ifabnormality found in related substanceschromatogram check the integrated parameters withthe blank.
Check the stability of the sample in analyte solution,repeat the injections. While doing the assaycalculate the values immediately, if the assay valuesare not meeting the specification or showing out oftrend the sample can be analyzed immidiately toverify the results.
So maintain the given temperature accurately.Ifabnormality found in related substanceschromatogram check the integrated parameters withthe blank.
Check the stability of the sample in analyte solution,repeat the injections. While doing the assaycalculate the values immediately, if the assay valuesare not meeting the specification or showing out oftrend the sample can be analyzed immidiately toverify the results.
How to report the (OOT) ResultsIf find any OOT results investigate the proper problem
(integration,calculation, dilution, etc). Repeat thesample analysis with the same solution,still it is anOOT results, inform to the incharge and go to freshor extra sample and analyse.
Still it is an OOT results report the first value. In thisway while conducting the stability studies thechemist or analyst should take all the precautionsbefore completion of the analysis and declaring theresults.
How to report the (OOT) ResultsIf find any OOT results investigate the proper problem
(integration,calculation, dilution, etc). Repeat thesample analysis with the same solution,still it is anOOT results, inform to the incharge and go to freshor extra sample and analyse.
Still it is an OOT results report the first value. In thisway while conducting the stability studies thechemist or analyst should take all the precautionsbefore completion of the analysis and declaring theresults.
By producing products with increasing shelf-life willbenefit the organization and give satisfaction to theanalyst who will conduct the stability program.
Evaluation of the results:1.Based on the 6 months accelerated or 12 months
long term stability study data, a 2 years shelf-lifemay be assigned for an API or intermediate product.
2.Final shelf life should be assigned to a productsupported by long term stability data.
By producing products with increasing shelf-life willbenefit the organization and give satisfaction to theanalyst who will conduct the stability program.
Evaluation of the results:1.Based on the 6 months accelerated or 12 months
long term stability study data, a 2 years shelf-lifemay be assigned for an API or intermediate product.
2.Final shelf life should be assigned to a productsupported by long term stability data.
Product Name:
Product No.
Batch No.
Mfg.Date.
Month as per schedule.
QA.issue No.
Date of analysis
Exp.Date.
S.No Name of the test Results Analysed By Date
1. Description1. Description
2. Water
3. P.H
4. Absorbance
5. Related substance
6. Assay
7. Additional test
Numbering for various categories of stability study isas follows.
UnitCode
Stability study
Stabilitycategory
ProductCode
Yearcode
Sequential noof protocol
E S ACC/LT/INT
Name oftheproduct
Name oftheproduct
