SOP Title: Procedure for Stability Study of Drug Products
- Objective:
To assure that products remain within specification for their shelf life it is necessary to have a systematic stability programme.
- Scope:
Product stability can be affected by changes to the formulation, method of manufacture, storage conditions and both raw material and contact packaging components. The procedure is applicable to all new / existing products manufactured.
- Products covered by stability requirements:
New Products
- Products where there is a significant change in:
Formulation
Manufacturing process
Packaging components
- Existing products kept as control samples.
- Responsibility:
QC Chemist: Responsible for analysis of stability samples and documentation as per SOP.
Head QC Department: Responsible for review of stability study data.
Head QA Department: Responsible for review, approval and ensure compliance of stability procedure.
- Accountability:
Head QC and QA Department
- Procedure:
5.1. Definitions:
Drug Product: The dosage form in the final immediate packaging intended for marketing.
Impermeable Containers: Containers that provide a permanent barrier to the passage of gases or solvent. e.g. sealed aluminum tubes for semi solids, sealed glass bottles for liquid preparations.
Semi permeable Containers: Containers that allow passage of solvent, usually water while preventing solute loss. Examples include plastic bags and semi rigid, low density polyethylene pouches and bottles.
New Product: New products are formulations, which does not exist in company .
Existing Product: Existing products are products which are existing in for a period of more than 2 years/ or for which minimum 10 production batches at manufacturing location has been completed whichever is earlier.
Existing products also include products with change in RM source of active/ excipients, change in process.
Long term stability study: This is a stability study set up to provide data to meet local regulatory requirements. It is to be set up to meet the requirements of stability study protocols as per ICH specifications.
Accelerated stability study: Used where an early indication of stability is required, or where a minor change in formula or packing is made. Also this test may be applicable to batches where the impact of reworking is being assessed.
Intermediate stability study: This method is used for the ongoing samples tested at an interval of 3 months up to 12 months due to specific changes to ensure that product is stable throughout its shelf life.
5.2 Procedure:
| 5.2.1 | General Procedure | ||||||||||||||||||||||||||||||||||||||||
| 5.2.1.1 | Incubators shall be maintained at ± 2° C of the specified temperature and ± 5% of the specified RH. This shall be monitored by use of chart recorders/ data loggers or recording in a logbook. The data loggers shall be reviewed fortnightly basis and as and when excursion takes place and any deviations as follows must be assessed for impact, recorded and reported to the Head of QA.
Deviations of > ± 2°C to ± 5°C from the set point for 48 hours. Deviations of > ± 5% RH to ± 10% RH from the set point for 48 hours. Deviations of > ± 5°C from the set point for 24 hours. Deviations of > ± 1 0% RH from the set point for 24 hours. |
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| 5.2.1.2 | The deviation if any should be discussed with the Head QA and informed to Contract Giver, if required. | ||||||||||||||||||||||||||||||||||||||||
| 5.2.1.3 | Additional test stations may be added where required. | ||||||||||||||||||||||||||||||||||||||||
| 5.2.1.4 | If the test is being set up to investigate a change to an existing formulation / process / packaging where possible at least one batch of the existing equivalent shall be set on concurrent test as a control sample. | ||||||||||||||||||||||||||||||||||||||||
| 5.2.1.5 | A sufficient number of samples should be maintained at each time/temperature point to allow for retesting of any parameter of batch found out of specification. | ||||||||||||||||||||||||||||||||||||||||
| 5.2.1.6 | Samples shall be collected from manufacturing area at defined staged as specified in the product BMR/BPR. | ||||||||||||||||||||||||||||||||||||||||
| 5.2.1.7 | The batches shall be charged for stability at both accelerated and long term conditions as per the regulatory requirement and technical agreement. | ||||||||||||||||||||||||||||||||||||||||
| 5.2.1.8 | Sampling shall be retrieved at defined time points. | ||||||||||||||||||||||||||||||||||||||||
| 5.2.1.9 | Analysis of the samples shall be carried out as per the finished product specification and method described in the current testing protocol and / or relevant pharmacopoeia. | ||||||||||||||||||||||||||||||||||||||||
| 5.2.1.10 | The Samples shall be withdrawn from the respective chambers at stated interval ± two days of the due days and tested as per specification. The samples shall be stored at 250C ± 20C until the completion of analysis. Remaining samples if any shall be destroyed as per SOP.
Deviations must be recorded, reviewed and approved by the Head of QA. |
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| 5.2.2 | Type of Batches Subjected for Stability Studies | ||||||||||||||||||||||||||||||||||||||||
| 5.2.2.1 | New product:
For all new products minimum three pilot batches with same batch formula shall be kept for accelerated as well as long term stability testing. First three production batches shall be kept for accelerated as well as long term conditions in the original marketed pack. |
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| 5.2.2.2 | Change in the Active Raw Material source/Excipients source:
Three production batches shall be kept for accelerated as well as long term stability studies and one production batch for change in excipients source. |
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| 5.2.2.3 | Existing products with New Pack:
Minimum one batch shall be kept for stability for both accelerated and long term testing. |
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| 5.2.2.4 | Existing product:
Minimum one batch of existing product annually shall be subjected for routine stability studies (25°C ± 2°C / 60% RH). To ensure that one batch is picked each year the first batch of the year should be picked for stability study. |
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| 5.2.2.5 | Pack:
All new as well as existing products has to be kept in final pack for stability studies |
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| 5.2.3 | Storage Conditions | ||||||||||||||||||||||||||||||||||||||||
| 5.2.3.1 | General Case (applicable for oral dosage forms – Tablets & Semi-solids – Ointments / Creams preparations packed in impermeable containers).
* Storage conditions for long term studies depend on the contract giver requirement of the particular agent.
** If 30°C ± 2°C / 65% RH ± 5% RH is the long term condition, there is no intermediate condition. |
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| 5.2.3.2 | 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.
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. melting of creams) may be expected under accelerated conditions; and, as appropriate for the dosage form. · Failure to meet the acceptance criterion for pH. · Failure to meet the acceptance criteria for dissolution testing at 12 dosage unit. |
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| 5.2.4 | Testing Frequency | ||||||||||||||||||||||||||||||||||||||||
| 5.2.4.1 | New Products :
* or up to after one month of expiry of product |
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| 5.2.4.2 | Existing Products:
For change in raw material / excipients source change in manufacturing location :
# For existing products long term study shall be performed above six months period of the shelf life. |
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| 5.2.5 | Stability Protocol | ||||||||||||||||||||||||||||||||||||||||
| 5.2.5.1 | Stability protocol shall comprise
· Objective · Scope · Responsibility · Procedure · Testing frequency · Testing parameter · Sample quantity · Test specification and method of analysis · Acceptance criteria · Report |
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| 5.2.6 | Analytical Testing Method | ||||||||||||||||||||||||||||||||||||||||
| 5.2.6.1 | In case of contract manufacturing products stability samples shall be analyzed by Contract Giver reference, there given finished product specification and validated analytical methods and should be stability indicating. The test and methods of analysis applicable along with reference to the specification number shall be indicated in the analytical section of the protocol. If any additional tests are required to be performed they shall be indicated in the analytical section of the protocol. | ||||||||||||||||||||||||||||||||||||||||
| 5.2.7 | Control of Studies | ||||||||||||||||||||||||||||||||||||||||
| 5.2.7.1 | A stability study may comprise several related batches, e.g. the first three production batches, current and modified pack/formulation etc. | ||||||||||||||||||||||||||||||||||||||||
| 5.2.7.2 | For each stability study a ‘Stability Study Set-up Record’ is to be prepared and should include the following information:
· Purpose · Batch nos. · Date of manufacture. · Date of primary packaging. · Date placed on stability · The number of units set on storage as determined using the table on the form. · The test methods are to be specified by reference to the approved procedure |
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| 5.2.7.3 | The number of units set on storage shall be determined using the table on the form. Sample removal at each time point and subsequent stock levels must also be recorded on the Stability Stock Record Sheet. | ||||||||||||||||||||||||||||||||||||||||
| 5.2.7.4 | When the stability test is set up a Stability Result Record is to be initiated for each batch/pack forming part of the stability study. | ||||||||||||||||||||||||||||||||||||||||
| 5.2.7.5 | Stability samples are to be clearly labeled with:
· Stability Study Number or Reference Number · Batch Number · Storage Conditions · Testing frequency due and placed in the relevant incubator. |
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| 5.2.7.6 | Regulatory approval shall be taken for the products which are under regulatory submission. | ||||||||||||||||||||||||||||||||||||||||
| 5.2.7.7 | The Set up and Results Records shall be passed to the responsible QC chemist for controlling stability tests. From these documents an annual test plan is drawn up. This plan is kept in the QC laboratory and is used to check the completion of testing. According to annual test plan a monthly test schedule shall be specified format. | ||||||||||||||||||||||||||||||||||||||||
| 5.2.7.8 | The chemist responsible for stability testing shall carry out or arrange the testing of the samples within 30 days of the due date. The analytical data, calculations and results shall be reported on the stability analysis record. Supporting data shall also be attached. | ||||||||||||||||||||||||||||||||||||||||
| 5.2.7.9 | The analysis record with associated print outs etc shall be checked by the QC Head or Senior Chemist and returned to the chemist responsible for stability studies. | ||||||||||||||||||||||||||||||||||||||||
| 5.2.7.10 | The analyst/chemist shall records the results on the Stability Results Record, which shall be checked by the QC Head or Senior Chemist and then forwarded to QA Department for review. This is to be done at each test point. | ||||||||||||||||||||||||||||||||||||||||
| 5.2.7.11 | The stability analysis records with associated data shall be filed with specific document number by the person designated for Stability Studies. | ||||||||||||||||||||||||||||||||||||||||
| 5.2.8 | Data Evaluation and Reporting | ||||||||||||||||||||||||||||||||||||||||
| 5.2.8.1 | The Head of QA shall review the stability results record at each test point. If the data shows little variation or degradation the results are accepted. If there is evidence of a trend statistical extrapolation is to be used particularly where accelerated testing is employed. The results record is returned to the analyst. | ||||||||||||||||||||||||||||||||||||||||
| 5.2.8.2 | For long term monitoring and where applicable accelerated testing, at each test
Point, a report shall be submitted to the Head QA for evaluation and review of proposed shelf life. The report shall include: · General product information. · Specification. · Test methods. · Study design and conditions. · Stability data and analysis of (including trend analysis). · Conclusions. |
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5.2.8.3 |
For long term monitoring where a result outside the existing or proposed specification is found, an OOS report shall be initiated as per SOP. | ||||||||||||||||||||||||||||||||||||||||
| 5.2.8.4 | If a failure is confirmed, additional batches or increased test frequency shall be implemented. | ||||||||||||||||||||||||||||||||||||||||
- Abbreviations:
| Abbreviation | Expansion |
| RM | Raw Material |
| ICH | International Conference on Harmonization |
| FIFO | First In First Out |
| RH | Relative Humidity |
| OOS | Out of Specification |
| AWR | Analytical Work Record |
| BMR | Batch Manufacturing Record |
| BPR | Batch Packing Record |
| 0C | Degree Centigrade |
*Note – Ready to use SOP available in “DOWNLOAD” Section.