SOP for Stability Study | ICH Guideline for Stability Study |
- Stability Study SOP covers below points:
- Stability Study definition
- Stability Long Term Testing
- Stability Accelerated Testing
- Established product
- Stable Product
- Stability Type of Climate and Zones
- Stability Climatic Zone and conditions
- election of Stability batches and Stability testing intervals
- Quantity of Stability sample
- Stability Test procedures and specification criteria
- Stability stations
- Stability sample Packing and labeling
- Stability sample storage and maintenance
- Testing of Stability sample
- Stability Documentation
- Stability sample Expiration date / shelf life
- Stability Study format
- Stability Study Sample Inward Register of Long Term Stability
- Stability Study Sample Inward Register of Accelerated Stability
- Format for Trend Data of Long Term Stability
- Format for Trend Data of Accelerated Stability
- Format for Temperature and humidity Record for Long Term
- Format for Temperature and humidity Record for Accelerated
- Format for Stability Study Protocol
- Label for Stability Sample
1.0 OBJECTIVE :
- To lay down the procedure for collection, storage and analysis of stability samples of finished product and estimation of expiration period.
2.0 SCOPE :
- This procedure is applicable to all experimental lots from F & D Department, Registration batches and commercial finished product.
3.0 RESPONSIBILITY :
- Quality Assurance Chemist and above
- Quality Control Officer and above for Analysis
4.0 ACCOUNTABILITY:
- Quality Control Head and Quality Assurance Head
5.0 PROCEDURE :
5.1 Stability Studies: Stability of product is the capability of formulation in specified container/ closure system to remain, within its physical, chemical, microbiological specifications. In other words, it is the extent to which a product retains, within the specified limits, throughout its period of storage and use, the same properties and characteristics possessed at the time of its packing. To provide evidence on how the quality of Finished Product varies with time under the influence by means of different environmental factors such as temperature, humidity, light and to establish storage conditions.
5.2 Long Term Testing: Evaluation of the physical, chemical and microbiological (if required characteristics of a drug product over the expected duration of the shelf life under recommended storage conditions and in the proposed container/closure system.
5.3 Accelerated Testing: Studies designated to increase the rate of chemical degradation or physical change of a drug product by using stress (exaggerated) conditions of storage. The basic objective is to reduce the time of study and extrapolate the result for the long term, i.e., till shelf life. The data provides tentative expiration date.
5.4 Established product: The drug product manufactured using a standardized process and formula and not showing significant change after assigned shelf life during long term stability testing and completed the accelerated stability study.
5.5 Stable Product: A product is considered to be stable when during long term stability testing the product is within specification limits up to its designated storage period and for accelerated testing there is no significant change in any parameter.
5.6 Stability data must demonstrate stability of the medicinal product throughout its intended shelf life under climatic condition prevalent in the target countries. Merely applying the same requirements applicable to other market could potential lead to substandard products.
5.7 The climate is different in all the countries in the world. Stability study should be done according to climatic condition of the country. According to the climate, world is divided into five different zones;
| Zone | Type of Climate |
| Zone I | Temperature zone |
| Zone II | Mediterranean / Subtropical zone |
| Zone III | Hot Dry zone |
| Zone IVa | Hot humidity / Tropical zone |
| Zone IVb | Hot / Higher humidity |
5.8 These zones are created due to difference in temperature and humidity. The climatic conditions for these zones are ;
- Long Terms testing conditions
| Climatic Zone | Temperature | Humidity | Minimum Duration |
| Zone I | 21°C + 2°C | 45 % RH + 5 RH | 12 Months |
| Zone II | 25°C + 2°C | 60 % RH + 5 RH | 12 Months |
| Zone III | 30°C + 2°C | 35 % RH + 5 RH | 12 Months |
| Zone IVa | 30°C + 2°C | 65 % RH + 5 RH | 12 Months |
| Zone IVb | 30°C + 2°C | 75 % RH + 5 RH | 12 Months |
| Refrigerated | 5°C + 3°C | No humidity | 12 Months |
| Frozen | -15°C + 5°C | No humidity | 12 Months |
- Accelerated and Intermediate testing condition
| Climatic Zone | Temperature | Humidity | Minimum Duration |
| Accelerated Ambient | 40°C + 2°C | 75 % RH + 5 RH | 6 Months |
| Accelerated Refrigerated | 25°C + 2°C | 60 % RH + 5 RH | 6 Months |
| Accelerated Frozen | 5°C + 3°C | No humidity | 6 Months |
| Intermediate | 30°C + 2°C | 65% RH + 5 RH | 6 Months |
5.9 This SOP covers Zone IVb (Hot and Higher humidity). Therefore, the studies are carried out at 30 °C + 2 °C / 75 % RH + 5 RH for long term and 40 °C + 2 °C / 75 % RH + 5 RH for accelerated condition.
5.10 As a general guidelines all new formulations, revised / improved products are the candidates for stabilities studies. However, because of uniqueness of each drug product it is virtually impossible to provide one set of rules that can apply to all situations. In view of this, the specific decision is taken at the situation of product and attributes.
5.11 SELECTION OF BATCHES AND TESTING INTERVALS :
- Carry out stability studies of development batches for a single or multiple batches as per formulation.
- Carry out stabilities studies of registration batches for three batches. Data on experimental batches provides supportive information.
- Container Size
- When the same product is marketed in more than one size, e.g., bottle containing 100 tablets and bottle containing 1000 tablets, it can be demonstrated by comparing the ratio of surface area of the container to the internal volume, that smaller container have a higher ratio than larger container. This indicates that the smallest marketed container is the most critical in terms of container properties contributing to product degradation.
- Thus, moisture or oxygen permeation through bottle for 100 tablets is more critical than through bottle for 1000 tablets of similar constructions.
- The selection of the study and testing should be based on the conclusions obtained from the respective investigation report.
- Note: The Long Term Stability of the Drug Product is to be carried out up to Shelf Life Plus 1 Year. If the Shelf life of product is 36 month, perform the long term stability up to 48 Month or for the product of shelf life of 24 months, perform long term stability study up to 36 months.
- If the product is manufactured on loan license, the stabilities study should be carried as per their requirement and communicate observations to Q.A. department of parent company.
5.12 SIGNIFICANT CHANGE :
- 5% change in assay from its initial value.
- Any degradation product exceeding its acceptance criteria.
- Failure to meet the acceptance criteria for appearance, physical attributes, and functionality test (e.g., colour, hardness, crack, pocket budging etc.)
5.13 BRACKETING :
- Develop reduced stability plan, in case of same product of different strength (dose proportionate average weight and same excipients) and multiple pack size.
- In this design stability schedule is worked out such that only sample of extreme case is selected. For example for a product having three strength 5 mg, 10 mg and 20 mg, select 5 mg and 20 mg.
5.14 QUANTITY OF SAMPLE :
- Receive the sample from IPQA Chemist which is intact marketed pack with carton.
- The quantity shall be equivalent to 700 tablets/capsules.
- Charge 200 tablets/capsules for accelerated study and 500 tablets/capsules for long term study.
5.15 TEST PROCEDURES AND SPECIFICATION CRITERIA :
- The testing should cover those physical, chemical and microbiological attributes, which are susceptible to change during storage and likely to influence quality, safety and efficacy of product.
- Prepare the stability study protocol for each drug product based on the standard test procedure.
- Update the stability study specification if the finished product specification is updated for major change or new method with better accuracy than earlier or as per regulatory requirement and follow the updated stability study specification for further intervals analysis.
- The specification should include Description, Identification, Purity (known, unknown, total impurities and degradation products) and Assay limits.
- The method of analysis needs to be stability indicating and validated.
- Each time the sampling should be from unopened container.
- Start testing as soon as possible without delay after it has been withdrawn.
- In case of unavoidable delays, freeze the sample until subjected to analysis.
- When it is not possible to collect a sample exactly at the designed time, the sample may be withdrawn conveniently and actual time of collection must be indicated in record.
5.16 STABILITY STATIONS :
5.17 PACKING AND LABELING :
- Collect the sample by giving intimation to production department of total quantity required for stability study and sub-divided into quantities required for each interval to carry out the tests indicated in the stability testing protocols and for the test intervals.
- The sample should be charged into the respective stability chambers on the day of commencement of the study as prescribed in the respective stability study protocol. The commencement date should be within 15 days of the date of approval of the batch which is considered as initial month.
- Place buffer samples (quantity sufficient to perform all the stability tests) for the purpose of cross checking in case of any deviations in storage or in case of spillage of material.
- The sample shall be packed simulating the dispatch conditions or as per the proposed packing in which it will be marked including primary and secondary packing and identified with a label showing the type of study.
- The label shall contain details such as date of charging, month of analysis, batch No. and also the instructions regarding the storage: Temperature and Relative Humidity (Refer Annexure No. 08).
5.18 SAMPLE STORAGE AND MAINTENANCE :
- A sample inward register should be maintained detailing the pertinent information required to plan the studies. For long term sample record (Refer Annexure No. 01) and for accelerated sample record (Refer Annexure No. 02).
5.19 TESTING OF SAMPLE :
- After completion of incubation period, withdraw the selected samples from stability chamber on due date and hand over to Q.C. Officer/ Executive.
- After the sample withdrawal from stability chamber, allow the sample to acquire the room temperature and then only start the analysis.
- Complete the analysis within 10 days after the withdrawal of sample. If the results are found to be Out of Specification, then carry out the investigation as per SOP of Handling Out of Specification.
- Inform the finding of result to Q.A. chemist.
- If the results are within the specification prepare the trend data of the Stability Study [Refer Annexure No. 03 for Long Term Stability, Refer Annexure No. 04 for Accelerated Stability]
- If in the prepared trend, the results are found to be Out of Trend, then carry out the investigation as per Handling of Out of Trend SOP.
- If any significant change is observed at accelerated stability study at any interval, analyze the samples of long term stability study.
- If any significant change is observed during stability study, discontinue the stability study and carry out the risk assessment study as per the Quality Risk Management SOP.
- Carry out the tests specified in the relevant stability study protocol (Refer Annexure No. 07), following the current stability study specification. The analytical method adopted should be stability indicating.
- Submit the completed test data sheet and the Stability Trend to technical Head for review.
5.20 DOCUMENTATION :
- Prepare Stability Study Protocol (Refer Annexure No. 07) for Long Term and Accelerated elevated conditions as per selection of batches and testing intervals.
- Stability analysis test data sheet shall be prepared according to the current specification. The analysis test data sheet shall contain details such as product name, batch number, batch quantity, manufacturing date, date of analysis, analysis details, signature of the analyst and date for each test and finally checked by and date.
- Stability Analysis Report shall be prepared on basis of Stability analysis test data sheet which contain the product name, strength, batch no., manufacturing date, pack size (container and closure), Type and Interval of Study, storage conditions, Reference Protocol Number, Analysis started on, Analysis completed on and purpose of study.
- Prepare separate trends for stability studies ( Long Term, Accelerated, conditions) as per respective Intervals as per,
- Annexure No. 03: Format for Trend Data of Long Term Stability (At 30°C + 2°C / 75% RH + 5 RH.)
- Annexure No. 04: Format for Trend Data of Accelerated Stability (At 40°C + 2°C / 75% RH + 5 RH)
- Attach the Instrumental raw data to the test data sheet of the stability studies, prepare the Certificate of Analysis and update the stability trends.
- File the Certificate of Analysis with test data sheet and Stability Trend in the appropriate file and label it properly.
- At the end of each year, prepare stability summaries for each product indicating the list of batches kept for stability, overall results of the completed intervals and the trend data for the critical parameters obtained which is the part of APQR of each product.
- Prepare stability summaries of drug products for which the stability study have been completed. Prepare graphs for critical parameters for presentation and reference.
- Note The temperature and Humidity of the Stability chamber twice daily. To record refer Annexure No. 05 for long term and refer Annexure No. 05 for accelerated.
5.21 EXPIRATION DATE / SHELF LIFE:
- An expiration date is defined as the time up to which the product will remain stable when stored under recommended conditions. Thus, an expiration date is the date beyond which it is predicated that the product may no longer retain fitness for use. If the product is not stored in accordant with the manufacturer instruction, will retain fitness for use (> 90 % of label claim).
- Recommend initially two years expiry. The life for future can be extended for third years only after real time data.
6.0 ABBREVIATIONS:
| Abbreviation | Expanded form |
| SOP | Standard Test Procedure |
| Q.A. | Quality Assurance |
| QC | Quality Control |
| APQR | Annual Product Quality Review |
| °C | Degree Centigrade |
| RH | Relative humidity |
| % | Percentage |
7.0 ANNEXURES:
| Annexure No. | Title |
| 01 | Stability Study Sample Inward Register of Long Term Stability (At 30°C + 2°C / 75% RH + 5 RH) |
| 02 | Stability Study Sample Inward Register of Accelerated Stability (At 40°C + 2°C / 75% RH + 5 RH) |
| 03 | Format for Trend Data of Long Term Stability (At 30°C + 2°C / 75% RH + 5 RH) |
| 04 | Format for Trend Data of Accelerated Stability (At 40°C + 2°C / 75% RH + 5 RH) |
| 05 | Format for Temperature and humidity Record for Long Term (At 30°C + 2°C / 75% RH + 5 RH) |
| 06 | Format for Temperature and humidity Record for Accelerated (At 40°C + 2°C / 75% RH + 5 RH) |
| 07 | Format for Stability Study Protocol |
| 08 | Format for Label for Stability Sample |
8.0 SOP REFERENCES
- ICH Guidelines
END OF THE SOP
ANNEXURES :
Annex. No. 01 Stability Study Sample Inward Register of Long Term Stability
Annex. No. 02 Stability Study Sample Inward Register of Accelerated Stability
Annex. No. 03 Format for Trend Data of Long Term Stability
Annex. No. 04 Format for Trend Data of Accelerated Stability
Annex. No. 05 Format for Temperature and humidity Record for Long Term
Annex. No. 06 Format for Temperature and humidity Record for Accelerated
Annex. No. 07 Format for Stability Study Protocol
Annex. No. 08 Format for Label for Stability Sample
