SOP FOR PROCEDURE FOR STABILITY STUDY OF FINISH PRODUCT
PURPOSE: The purpose of this SOP is to describe a procedure for stability study of Finish products.
SCOPE: This SOP is Applicable for stability study of Finish products.
RESPONSIBILITY: QA personnel shall be responsible for the preparation of the SOP and stability protocol.
QA personnel shall be responsible for charging and withdrawal of stability samples as per protocol and planning.
QC personnel shall be responsible for the review of stability protocol and sample analysis planning.
QC personnel shall be responsible for analysis of stability sample, review of stability summary report.
QC Head/ Designee shall be responsible for review of the SOP.
QA personnel shall be responsible for the review and approval of the SOP.
QA Head/ Plant Head/ Designee shall be responsible for authorization of the SOP.
ACCOUNTABILITY: The accountability, implementation and compliance of the SOP is HOD-Quality Assurance.
PROCEDURE:
To conduct Stability Study: To monitor and study any chemical, physical, biological and microbiological (if required) attributes of drug products when exposed to various storage conditions during their life cycle. This shall provide evidence how the quality of drug product varies with the time under the influence of a variety of environmental factors.
To confirm and assure the quality, safety and efficacy of the drug products in their marketed/ proposed packs during warehousing, distribution, storage and use throughout its life cycle.
To evaluate the batches where the change control affected to quality of drug product.
To conduct routine evaluation of existing commercial/ validation batches.
To generate supporting stability data for product registration in various countries.
Stability Study Protocol Preparation
Stability study protocol shall be prepared by QA as per Format No.SOP/C/QA056-F05 reviewed by QC, QA and approved by QA Department for each product before charging a product for stability study.
Stability study protocol shall also be considered as Stability study “Protocol cum report”.
QA Department shall assign the number to stability protocol as SP/YY-NNN,
Where; “SP” Denote the Stability Study Protocol.
“/” Denote the separation
“YY” Denote last 2 digits of the manufacturing year of product.
“-” Denote the separation.
“NNN” Denote the Serial number
Addendum to Stability Protocols: An Addendum to stability protocol shall be issued based on the queries and justification received from any regulatory agency for modification of acceptance criteria of any analytical test parameter or inclusion of any new test parameter.
An amendment to stability Protocol shall be issued if any change/variation is made at any time during the conduct of the stability study program.
An amendment to stability Protocol shall be issued if there are any changes in stability storage condition due to any observed significant changes.
Storage Conditions: Storage conditions shall be based on the International climatic zone or as per specific country guidelines. A storage statement should be established for labeling in accordance with relevant national/ regional requirements. The statement should be based on the stability evaluation of the drug product. The specific requirement is described in the following matrix.
For Storage “General Condition”
| Storage condition | Temperature (°C) | RH (%) |
| Long Term | 30±2 °C | 75±5 % |
| 25±2 °C | 60±5 % | |
| Intermediate | 30±2 °C | 65±5 % |
| Accelerated | 40±2 °C | 75±5 % |
For Products Storage condition Labeled as “Store in Refrigerator”
| Storage condition | Temperature (°C) | RH (%) |
| Long Term | 5±3 °C | — |
| Accelerated | 25±2 °C | 60±5 % |
Storage condition shall be based on the international climatic zone as per the specific country guidelines or the ICH guidelines, which provides specific requirements for :
General case
Drug products packaged in impermeable containers.
Drug products packaged in semi-permeable containers.
Drugs products intended for storage in a refrigerator.
Any other additional or specific storage condition requirement may be applicable based on country/ regional requirement.
Where a “significant change” occurs during storage under accelerated condition (40±2°C/75±5% RH or other applicable accelerated condition), discontinue the accelerated study and initiate the Intermediate storage condition or other stringent storage condition.
“Significant change” for a drug product at the accelerated stability condition and the intermediate condition is defined as
A 5% change in assay from its initial value or failure to meet the acceptance criteria for potency as defined in the stability protocol/specification.
Failure of the stability sample to meet the acceptance criteria for appearance, physical attributes, and functionality test.
Any degradation product’s exceeding its acceptance criterion.
Failure to meet the acceptance criterion of pH.
Failure to meet the acceptance criteria for dissolution for 12 dosage units.-
Accelerated study may be continued for investigation and data collection, if required.
Test Station
Stability study shall be carried out as per the following test station.
| Station | Accelerated | Intermediate* | Long term |
| **Initial | NA | NA | NA |
| *** 1 Month | Yes | NA | NA |
| 3 Months | Yes | Yes | Yes |
| 6 Months | Yes | Yes | Yes |
| 9 Months | NA | Yes | Yes |
| 12 Months | NA | Yes | Yes |
| 18 Months | NA | NA | Yes |
| 24 Months | NA | NA | Yes |
| 36 Months | NA | NA | Yes |
| 48 Months | NA | NA | Yes |
*Applicable when accelerated study does not comply.
** Initial point is the results at release for finish product analysis.
***1st month study shall be carried out as per Customer Requirement (if any).
Note: Study shall be continued for one year after the expiry of the product.
Test Specification and Test Procedure: For Pharmacopoeial Products: Compendial limits are applicable during stability study. Any change in the specification calls for amendment in stability protocol.
Stability specifications shall include parameters, which are susceptible to change during storage and can affect the quality, safety and / or efficacy of the product.
Analysis of sample shall be carried out as per the respective STP or as per the test method prescribed in the respective stability protocol.
Test for assay and related substances of the product under stability study shall be carried out using an analytical validated method and compendial method to respective product.
If the stability assay method is different from the product release assay method, then assay at release shall be re-performed as per stability method.
Additional tests, if any, other than those mentioned in the stability specification as per stability protocol, shall be performed at the time of charging the samples.
Selection of Batches and Number of Batches
Selection Criteria: Approved batches as per release specification shall be selected for formal stability study.
Batches to be selected for stability shall be representative of manufacturing process either pilot plant or full production scale.
Number of batches: Three consecutive batches of established manufacturing process/ new product shall be kept for format stability studies.
Every year first batch of each product shall be kept for ongoing stability studies.
For existing product keep three batches for stability study whenever the following changes occurs.
A primary packing component is changed.
A significant manufacturing process change is made or planned to be made for a given product.
A significant change in manufacturing equipment such as blender and granulator etc. is made, which may influence product quality.
A significant process scale up is made which could have influence on product quality.
Change in Active Pharmaceutical Ingredient (API) source from approved vendors/change in manufacture site of approved vendor.
Regulatory agency requirement demands a particular stability study to be performed.
An evaluation is needed to study the influence of storage during transportation on the quality of a given raw material or finished product (Transportation study).
Additional stability studies may be carried out for market returned products, complaint samples, samples collected from different sale depots, areas in market as per the directives received from Head QC and Head QA.
Stability samples shall be put to bracketing study if the strength is identical.
Preparation and charging the sample: Stability Sample shall be collected in same container closures system, which represents the market/ proposed market pack.
Collect sufficient quantity of sample as calculated for 1.3x of analysis as per the testing procedure for process validation or exhibit batches. For 1st batch of the year one station additional sample shall be kept for investigation purpose.
QA personal shall withdraw the stability sample as per the schedule and submit the samples to QC for analysis through a Stability Study Intimation sheet.
QA personal shall enter the sample details in the Stability Sample Issuance Record.
QA personal shall give Drug Product and Component Detail along with stability samples.
Separate sample shall be prepared for each station for physical, chemical and microbiological testing (if applicable) which shall be kept in stability chambers.
Combined set (double quantity) of samples for each station are charged for stability study. One set of samples used for regular stability analysis and another set of samples to be analyzed for investigation (OOS) of failure samples during stability studies (The same shall be destroyed after completion of the testing).
All stability samples (station wise) shall be identified with proper labeling.
All stability samples (strips and vials) shall be identified with different label for different conditions.
Sample shall be prepared as per the approved stability protocol.
Samples shall be charged for stability studies within 30 days after the release of the batch.
If it is delayed for more than 30 days, then the sample shall be reanalyzed for initial results (otherwise samples shall be destroyed of initial stage).
The release / re-test results shall be used as initial data of test parameter for compilation.
In-charge/designee stability room shall charge the sample in the appropriate stability chambers in line with the stability conditions mentioned in the stability protocol and the same shall be recorded the Stability samples Inward and Outward Log.
Monthly planner for withdrawal of stability sample shall be maintained.
Temperature and Humidity recording of Stability chamber shall be recorded on one hour time interval. Printout for the same shall be taken daily basis.
In case of failure of the chamber for more than one day, the samples shall be transferred in another standby chamber, which has been qualified at the same condition (Temperature and RH).
Sample withdrawal for testing: We identify sample as per monthly stability planner and shall be withdrawal on its schedule frequency.
The In-charge/ designee stability room shall withdraw the sample within +3 days of due date in case of accelerated stability studies and within +7 days of due date in case of long-term stability studies.
After withdrawing the sample from the stability chambers, QC shall allocate the A.R. No. (for initial stage analysis and thereafter every interval analysis “A.R. Numbering procedure in Quality Control Laboratory”) and all the entries shall be made in the stability samples date out log.
Samples under accelerated conditions shall be withdrawn from the stability chamber at stated interval (within 3 days of the withdrawal date), stored the sample at recommended storage conditions and at the designated place in the laboratory and tested within +20 days for chemical, physical analysis and microbial analysis.
Sample under intermediate conditions shall be withdrawn from the stability chamber at stated interval (within 7 days of the withdrawal date), stored the sample at recommended storage condition and at the designated place in the laboratory and tested within +30 days for chemical, physical analysis and microbial analysis.
Samples under long-term conditions shall be withdrawn from the stability chamber at stated interval (within 7 days of the withdrawal date), stored the sample at recommended storage condition and at the designated place in the laboratory and tested within +30 days for chemical, physical analysis and microbial analysis.
List of authorized persons to Access the stability chamber.
Authorized person shall make the entry of stability chamber opening and closing in “Stability chamber user Access Logbook”.
Compilation and Reporting: The Raw date of Stability study shall be recorded in analytical data sheet analyst. All the results shall be entered in the product specific report.
Analytical data sheet and supporting data like chromatograms / spectra / graphs, etc. shall be checked by second person for correctness of results, calculations with sign and date. The analytical data sheets shall be reviewed as per the Respective SOP.
Results of products at each station of stability study, trend report shall be prepared as per reference SOP. The results found during the stability study outside the specified range of the product specification shall be considered as out of specification result.
Any results found outside the trend then shall be investigated as per SOP. Any abnormal trend or any adverse change or showing faster deterioration of product shall be reported immediately to Head QC, Head QA, Head- Manufacturing and Head- F&D.
Investigation of OOS/OOT shall be done as per SOP of “Handling of Out-of-specification and Out-of-trends test results”. Any confirmed out of specification result, or significant negative trend, affecting product batched released on the market should be reported to the relevant competent authorities.
Decision shall be based on the outcome of the investigation by QA. Further QA shall inform to other concern department Head for necessary action.
In case the stability study needs to be discontinued then In-charge/designee stability room shall fill the stability discontinuation authorization form, which is approved and authorized by Head QC and Head QA.
After completion of the program a general review of the stability data shall be conducted to justify any change in current expiration date.
The compilation of the results of accelerated/ intermediate stability data shall be recorded.
The compilation of the results of long-term stability data shall be recorded.
Evaluation of Stability Data: As per the ICH guideline Q1E the initial expiration date of new drug product shall be justified based on accelerated stability results.
Based on the 6 months accelerated data or 12 months Long term data (X), a 2 year shelf life (Y) may be assigned for the drug product but not exceeding 12 months, e.g. Shelf Life (Y) = Upto 2(X) Long term data, but not exceeding (X)+12 months. (Refer Appendices A of ICH QE). This is applicable as long as the stability data showing no significant variability over the time (only for storage in room temperature storage).
Extension of shelf life shall be decided on the basis of Long-Term stability Data. A minimum of three completed Batches are needed.
Based on the review of stability data, recommendation (if any) for the change of stability parameter, analytical methods, storage conditions shall be communicated to QA and manufacturing.
Action in case of validation / break down: If the variation in temperature for humidity condition set for the stability chamber happens ‘Alarm’ is sounded. Attend the instrument immediately and inform to stability incharge.
REFERENCE:
WHO Technical Report Series, No. 1010, 2018
ICH guideline: Stability Testing of New Drug Substance and Products Q1A (R2)
ICH guideline: Evaluation of Stability Data Q1E
SOP FOR SOP
Handling of Out-of-specification and Out-of-trends test results