OBJECTIVE :
This document describes the process and requirements for the stability Studies including: stability study, including ;stability protocol, batch selection, storage conditions, testing frequency, study set up, study management, stability withdrawal, stability testing, data evaluation, data trending, study termination and estimation of shelf life.
RESPONSIBILITY :
1.0 Section Head or Designee:
1.1 Maintaining the sample records, including the logging of sample receipt, distribution, and destruction.
1.2 Maintaining the samples in the designated and secure location before distributing to Analysts for testing and after testing until the remainder of the samples are properly destroyed.
1.3 Informing to QC Head if discrepancies identified with sample reconciliation or unusual observations with the samples.
1.4 To pull out the stability samples from stability chambers as per the planner/schedule.
1.5 To create the stability study protocols in conjunction with the initiating department and obtain approval signature and issue Stability template or stability test data sheet for analysis.
1.6 Ensure all the stability chamber is qualified, monitored and suitable for intended use.
1.7 Verification of the stability sample charged at different storage conditions and secures the location before distributing to analyst for testing and after testing until the remainders of the samples are properly destroyed.
1.8 Maintain a sample log for all the stability samples and perform a periodic inventory to sure accountability of stability samples.
1.9 To initiate the OOS/OOT investigation, if observed.
1.10 To issue the stability template to analyst as per SOP.
1.11 To prepare and update stability summary report and update all the documents related to stability.
1.12 To establish an easy retrieval and secure archiving procedure of stability documents.
1.13 To inform QA to collect required number of samples (units) for stability study as per the requirement of the stability protocol. Charging of samples at condition(s) recommended in the respective stability protocol.
2.0 Analyst
2.1Ensuring sample integrity during testing.
2.2 Performing analysis on stability samples following documented test procedures.
2.3 Immediately notify management of discrepancies, unexpected, or unusual observations, data or events. Participating in investigations, if applicable.
3.0 Head QC or Designee
3.1 To approve the stability protocol
3.2 To ensure the proper implementation of SOP.
3.3 To review and approve the stability summary report, Discontinuation, Trend and evaluation of stability performed.
3.4 Ensuring a secure location for stability samples with access and environmental controls.
4.0 Quality Assurance
4.1To provide the intimation to Quality control department for preparation of stability study protocol.
4.2 To identify the need for a stability study.
4.3 To collect the stability samples from manufacturing area in its final pack as per the quantity prescribed in stability protocol and submit the samples to analyst stability of Quality Control Department along with stability test request.
4.4 To evaluate and recommend the shelf life of drug Products
5.0 PROCEDURE
5.1 Pre-submission / Exhibit Batches
5.1.1 Drug Substance – The batches shall be manufactured to a minimum of pilot scale by the same synthetic route and method of manufacture that simulates the final process to be used for production batches. The quality of the stability drug substance batches shall be representative of the quality of production scale material.
5.1.2Drug Product – The batches shall be of the same formulation, container-closure system, and manufacturing process that simulate those conditions to be applied to production batches. Two of the three batches shall be at least pilot scale batches and the third batch can be smaller, if justified. Where possible, batches of the drug product shall be manufactured by
5.1.3 Post-commercialization (or Annual Batch): The determination of the number of batches to be placed on stability annually shall be proceduralized. In addition, the process by which the annual lot(s) are identified shall be described and the individuals involved in the process defined.
5.1.4 Special Cases: Batches manufactured with changes to the formulation, manufacturing process, batch size, packaging components, drug substance, etc., shall be placed on stability. The stability batches shall be representative of the production batches. In addition, if a deviation/investigation warrants commercial batches/lots to be monitored, the applicable batches/lots might be placed in stability program.
5.1.5 Container-Closure Systems: Stability testing shall be conducted on samples (i.e., drug substances, key intermediates, and drug products) packaged in the commercial container-closure system or the container-closure proposed for marketing or storage, including any secondary packaging and container label, as applicable.
6.0 Initiation of Stability Study
6.1 To ensure the stability data generated are reliable, meaningful and meeting regulatory expectation the stability program must consider all aspects regarding the controls and management of samples as well as test data.
6.2 The stability initiation form created by the QA department and made available for use when requesting the stability studies to be performed on a selected batch/lot. Stability samples of Product are collected by QA department and provided to QC department along with Stability Test Request. Verify the details on sample against the received “Stability test request’’ from QA department.
6.3 The stability initiation form include name, signature and date of both the requestor and stability coordinator and sample details, Mfg date, Exp date sample quantity, packaging Configuration, stability study Protocol. No, required storage condition.
6.4 Keep initial three validation / exhibit batches in required finished product as per approved stability study protocol.
6.5 Keep one batch per year (if manufactured) subsequently for long term stability study (follow up stability study). No additional time point shall be considered to stability data generation on annual addition batches or post approval commercial batches except where there is a specific requirement of shelf life extension.
6.6 Conduct stability testing on the dosage form packaged in the container closure system proposed for marketing (including, as appropriate, any secondary packaging and container label).
6.7 Consider first three batches for Long term, and Accelerated stability. (“First” means the product is manufactured for the first time at the site ). Batches should be of the same formulation and packaged in the same container closure system as proposed for marketing.
6.8 In case of new product, samples of three consecutive batches shall be kept for Accelerated and long term stability studies.
6.9 In case of specific requirements, QA shall provide the samples to QC for stability analysis accordingly along with intimation.
6.10Any batch manufactured in the last week of the previous year shall not be considered or selected for annual stability study for that batch selected manufactured and packed in the same year.
6.11 The status of on-going stability should be periodically reviewed (at least once a year).The stability study followed ,number of batches incubated ,reason for monitoring, condition of Stability chamber any excursion or deviation in stability trend, stability failure but not limited to should be evaluated and appropriate action if required should be initiated.
6.12 Each protocol shall be assigned a unique identification number. At a minimum, the protocol shall include the following required elements, purpose/reason, reference, product description, container closure/packaging configuration, storage conditions (i.e., temperature and humidity), sample orientation (i.e., upright, inverted and side-ways as applicable), time intervals, number of samples required, stability tests, test method references.
6.14Each stability protocol shall be reviewed and approved by all responsible departments (e.g., Initiating Department, Stability In charge QC, QC/Designee Head, and QA Head/Designee).Mandatory signatures for all sites shall include Research and Development Department if applicable.
7.0 Sample Size:
7.1 Sample shall be collected as an intact-marketed pack. The quantity of sample collected shall be in sufficient number depending upon the product and its stability indicating test.
7.2 Generally the number of sample will be as follows.
7.3
| Category | Stability Storage Condition | Selection of Batches |
| New drug product | Long Term | First three batches |
| ACC Condition if applicable as per criteria | ||
| Annual addition Batch | Long Term | One Batch |
| Change In Primary Packing | Long term & ACC | One Batch |
| Change in source of API (Vendor change) | Long term & ACC | One Batch |
| Change In Component & Composition | ||
| Formulation Change: Those changes are those that could have a significant impact on formulation quality and performance. The total additive effect of all excipient changes should not change by more than 10% | Long term & ACC | One Batch |
| Change in Batch Size | ||
| Change in batch size up to including factor of 10 times the batch size of pilot batch | Long term | One Batch |
| Change In batch size beyond the factor of 10 times the batch sizes of pilot batch. | Long Term & ACC | One batch |
| Change In manufacturing Equipment | ||
| Changes in equipment to different design and different operating principle Changes from non-automated to automated equipment or alternative equipment of same design and operating principles of any capacity | ACC & Long term | One Batch |
| Changes in the Specified manufacturing Process | ||
| Changes involving adjustment to equipment operating condition outside the original approval range | Long Term & ACC | One batch |
| Change in type of process | Long Term & ACC | One batch |
7.4 Collection of stability Samples
7.4.1 QA shall withdraw stability samples randomly during online packing after verifying in-process checks.
7.4.2 QA shall ensure that samples collected are intact in the marketed pack
7.4.3 After sampling QA shall send the sample to QC along with stability test request form.
7.4.4 QA shall refer or confirm the stability sample quantity from stability protocol.
7.4.5 Only one set of samples shall be collected for each stability condition for products intended for different markets that have same formulation (recipe, manufacturing process and primary container & closure system).
7.5 Reciept of Samples
7.5.1 Drug Product samples intended for commercial stability studies shall be received in the approved marketed packaging configuration. For exhibit batches, sample shall be collected for stability studies in the proposed marketed primary packaging configuration. Stability samples shall be received by stability group.
7.5.2 Stability group from QC shall verify the sample the stability initiation form & stability protocol (as applicable)
| No. of Analysis (Stability stations) | × | Quantity required for ONE analysis including Microbiological analysis whenever required | + | 1 extra Quantity required for Accelerated condition and 3 extra Quantity required for Long term condition of single analysis (In case of OOS or other analytical issue) |
and enter the details in the stability sample Receipt log upon receipt
7.5.3 At a minimum, the following shall be documented and tracked in the stability sample Receipt Log: date of receipt, Product name, Batch number, strength, Pack (if applicable), Market, Manufactured date, Expiry/retest date, Protocol. No, Quantity/No. of samples received, sample received. Information regarding the use of Contract Laboratories, as applicable, for all aspects of shipment for storage and/or testing shall be documented in detail.
7.5.4 After receiving the stability samples, sample shall be stored at respective products storage condition until incubation.
| No. of Analysis (Stability stations) | × | Quantity required for ONE analysis including Microbiological analysis whenever required | + | 1 extra Quantity required for Accelerated condition and 3 extra Quantity required for Long term condition of single analysis (In case of OOS or other analytical issue) |
In case where sample required for the additional testing (Significant change), entry of the same for the withdrawal shall be made in “Stability Sample Reconciliation and Destruction logbook”.
7.6 Stability Storage Conditions / Testing Frequency
7.6.1 Storage conditions and the lengths of studies chosen shall be sufficient to cover storage, shipment, and subsequent use throughout the labeled shelf-life.
7.6.2 Stability storage conditions shall take into account the intended market and the climatic conditions in the country in which the product should be distributed.
7.6.3 Climatic zones with definition and storage conditions are as follows Refer Table 2 for different temperature and humidity conditions for the Long term and Accelerated as follows.
| Climatic Zone | Definition | Stability condition | |
| Accelerated | Long term | ||
| I | Temperate Zone | 40±2ºC/75±5%RH | 25±2 ºC/65±5 %RH |
| II | Sub-tropical Mediterranean Zone | ||
| III | Hot and Dry Zone | 40±2 ºC/75±5%RH | 30±2ºC/65±5 %RH |
| IV A | Hot and Humid Zone | ||
| IV B | Hot and very Humid Zone | 40±2ºC/75±5%RH | 30±2ºC/75±5 %RH |
| Study | Testing Intervals (Months) |
| Long Term | Initial, 3, 6, 9, 12, 18, 24, 36, 48, 60 |
| Accelerated | Initial, 3, 6 |
Testing Intervals for Stability Testing (For Commercial Stability, i.e. Annual Addition Batches)
| Study | Testing Intervals (Months) |
| Long Term | Initial, 6, 12, 24, 36, 48, 60 |
| Micro Testing Long Term | Initial, 6,12,24,36 |
| Micro Testing Accelerated | Initial, 6 |
7.7 Stability Sample Scheduling and Withdrawal:
7.7.1 Samples shall be charged on stability (Date-in) within 15 calendar days from the date of receipt.
7.7.1 In case the number of days is beyond 30 calendar days, the parameters mentioned in the stability protocol shall be tested again. The results obtained shall be considered as initial testing results/Time Zero (T0) Testing Data.
7.7.2 The date of the stability sample withdrawal shall be no later than + 5 calendar days. For example, if the date on stability is June 6th, the 3-month test interval shall be withdrawn on September 6th. In the event that September 6th falls on a non-business day, then it shall be withdrawn on the next business day, not to exceed September 11th.
7.7.3 After withdrawing the sample from the stability chamber, the stability samples shall be held at the labelled storage condition of the product (for example-controlled room temperature, cool, cold, etc.) till the time they are taken up for testing by responsible person.
7.7.4 Expiry Testing: In case of commercially distributed batch on stability, last testing interval shall be performed at time point representative of expiry date of the product.
8.0 Stability Sample Testing
8.1 Analysis of samples must be completed within the appropriate time frames.
8.2 For Samples with OOS/OOT/LEQ/LENQ and impact batches, the time line for Completion of completion of Chemical analysis, review and approval shall be considered as per timeline QMS of record generated.
8.3 In case of missed stability station next subsequent stability station or any additional station analysis shall be conducted and actual time of analysis shall be mentioned in stability summary report. Missed station shall be mentioned as “Missed Station” in the stability summary report and handle through QMS.
8.4 If the stability sample analysis of all tests or specific test is not completed within the stipulated time period, a deviation to be logged as per Site Specific procedure.
9.0 Stability Study Protocol Preparation:
9.1 Stability Study Protocol numbering to be done as SP/001/25(001 stands for serial number of stability Study Protocol, 25 stands for the year) i.e. First Stability Protocol named as SP/001/YY and so on.
9.2 Revised Stability Protocol named as SP/001/01, 01- Stands for revised protocol and so on.
9.3 If editorial Changes are applicable to stability, the stability Study Protocol number as SP/001/E1, E1 Stands for Editorial change.
9.4 Stability Study Protocol Shall be prepared by Stability Section Head, checked by the designated person and approved by the Head quality assurance.
9.5 Stability Study protocol shall be designed such a way that it provides the information about the Purpose, Scope, Procedure (Stability Conditions (Accelerated & Long-Term Condition).
9.6 Stability Study Programme (Stability Sample and testing time points for chemical analysis, Stability Sample and testing time points for microbiological analysis, Chemical Stability test analysis and Microbiological test analysis.
10.0 Data Evaluation and Trending
10.1 A systematic approach shall be used for summarization, review, and approval of all stability data with responsible individuals identified.
10.2 During the course of accelerated stability testing, if there is a “significant change” or failure of any quality attributes at any time, additional testing at the sample stored at controlled condition to be done.
10.3 Significant change for a drug product is defined as:
10.3.1 A 5% change in assay from its initial value or failure to meet the specification.
10.3.2 Any degradation product(s) exceeding its specification.
10.3.3 Failure to meet the specification for appearance, physical attributes, and functionality test (e.g. color, phase separation).
10.3.4 Failure to meet the specification for pH.
10.3.5 Loss of potency for Vitamin products should not be considered
10.4 Study Completion and Termination:
10.4.1 Upon completion of a study, the actions to be taken include, but are not limited to, submission of the final stability data summary sheet to laboratory management, generation of the Final Stability Report and review and approval of the report by all applicable departments, such as Initiating Department, QA, Quality Control/R&D, Technical Services, etc. as applicable.
10.4.2 Stability Data Summary Report: A final stability report shall be generated for each stability study. All stability data for each time interval and all tests shall be documented in the report, which also includes, at a minimum, product description; product lot number; package size; storage conditions and sample orientation; container/closure description; stability protocol number; study initiation date; manufacture date, as applicable; expiration date, as applicable. data tables; data summary; data trending; analyst, date of analysis, reference of OOS/OOT investigations/deviation reports, if applicable; stability chamber excursions, if applicable; and review and approval signatures.
After completion of the stability scheduled/study of batch analysis (All time points), the stability section In charge shall remove all remaining samples of that batch from their respective Chambers and keep the samples at controlled room temperature, with status label ‘Sample to be destroyed’. After confirming the final status of batch, destroy the excess samples.
10.4.3 In case of change in manufacturing process/ and or formula of the product, Ongoing stability batches shall be continued with applicable specifications and test Procedures, if the Product is Commercialized.
10.5 Stability Chambers:
10.5.1 The controlled access, qualification, use, and monitoring of temperature and humidity of the stability chambers, including the responsible individuals shall be described in Site-specific written procedures as follows:
10.5.2 Stability Chamber shall be fitted with alarm system to notify the staff to take the appropriate action in case of excursion where in the condition (Temperature and Humidity) in general case go out of acceptance tolerance level ±2°C in temperature and ±5% in relative humidity.
10.5.3 Excursion that defined the tolerance limit for more than 24 hours shall be handled in accordance with site specific deviation management procedure and assessment shall be made of the impact on ongoing stability studies.
10.5.4 There shall be a contingency plan in place for stability sample storage in the event of extended malfunction/ maintenance event.
10.5.5 In case of natural calamity, if chamber is shut down for few days impact analysis shall be done as per the following criteria.
10.5.6 Consider one batch of the lowest label claim and one batch of highest label claim.
11.0 REFERENCE :
Drug and Cosmetic Act
WHO & ICH guideline