LAB-130 Stability Management Procedure

5.1 Overview of Annual Stability Program

5.1.1 Ongoing Stability

The Stability Team Leader / Designee is responsible for updating the On-Going Stability Product Order Form (Form 735).

This form contains but is not limited to the following information:

Product Name / Strength Packaging Size Packaging Material

Total Amount Required (including spares, time 0 and micro) Amount Required per Micro Timepoint Storage Conditions Expiry Period (months) Testing Laboratory Department Sample Requested from Sample Ordered By / Date Sample Received By / Date

This form should be updated if a product is discontinued or if a new product is manufactured.

The Stability Team Leader must be notified by the QA Department if a product is discontinued.

5.1.2 Production Stability

5.1.2.1 Production stability may be required in cases such as change in the manufacturing procedure, change in raw materials, change in packaging for regulatory purposes, troubleshooting or reworked batches.  It is the responsibility of the QA designee to determine if a stability study is required.

5.1.2.2 Prior to commencement of any changes in the manufacturing procedure a Validation Trial / Alert Form should be issued indicating whether or not Stability

Testing is required on the product.  If stability testing is required a copy should be sent to the Stability Team Leader or designee.

5.1.2.3 When stability testing is required, a Stability Program Protocol must be completed by the QA Designee with details of the change as well as the tests, conditions and time points required.  The protocol must be signed by the Stability Team Leader or designee.

5.2 Obtaining Stability Samples

5.2.1 Obtaining Ongoing Stability Samples

5.2.1.1 At the start of each year, the Stability Team Leader / Designee prints out a copy of Form 735 and records the current year on it.

5.2.1.2 The “Sample Ordered By / Date” on Form 735 must be filled out when the samples are ordered.

5.2.1.3 The amount of sample required is requested from the appropriate department using Form 730 Sample Request Form for Stability Program.  The sample amount required is taken from Form 735.

5.2.1.4 Ongoing Stability Products can be ordered throughout the year when packaging is completed, unless otherwise specified where a specific batch is requested.

5.2.2 Obtaining Production Stability Samples

The amount of sample required is calculated from the testing and time point requirements as per the Stability Program Protocol created by the QA designee.  The sample is requested from the appropriate department using Form 730 Sample Request Form for Stability Program.

5.3 Receiving Stability Samples

5.3.1 For Ongoing Stability samples the Stability Team Leader or designee must record the date the samples are received on Form 735 when the stability samples are delivered to the Laboratory.  This form must be reviewed quarterly in partnership with other impacted departments to ensure all required products are on track to be entered into the stability program for the year.

5.3.2 Upon received, all Ongoing and Production Stability sample details must be entered into the Scheduling of New Samples to be Placed On Stability Program Logbook.  The logbook typically contains but is not limited to the following headings:

Product Name & Strength

Lot No.

Initial Testing Completion Date

Time 0 Required (Yes/No)

Packaging Date

Study Initiation Due Date

Actual Study Initiation Date

Initial and Date on Study Initiation

5.4 Stability Study Initiation

5.4.1 Upon receipt of stability samples, the Stability Team Leader or designee will generate a Stability Protocol and Reports for the study.  These documents will include the following information:

Study ID (i.e. unique identifier)

Product name and strength / concentration

Lot number

Manufacturing date

Lot expiry date

Maximum Product expiry period

Reason for study

Registration specification / Approved Documents

Study type

Study commencement date

Packaging details

Storage conditions including temperature and humidity

Test points (at least annually and at their true expiration date)

Tests to be performed

Acceptance criteria or a reference to the acceptance criteria

Special instructions

Signature of the author

Signature of approval

The Protocol Number is expressed in the following format:  XXXXX-YYT-NNN

Where: XXXXX is a code for the Product e.g. ABC10 – ABC 10 mg Tablet;

YY indicates the year of manufacture for the lot;

T indicates the stability study type,

P for Production or O for Ongoing;

NNN is a sequential number starting at 001 and reset at 1 January each year.

5.4.2 The stability study should be created in the stability database.  The Stability protocol and reports are created with reference to the Registered Specifications, Stability Program Protocols and/or any other approved documents.

5.4.3 The Stability Team Leader or designee will print out the Stability Protocol and Reports and sign and date them.  The signed documents will be forwarded to the Laboratory Manager or designee for approval.  The Laboratory Manager will check the documents to ensure all details are correct as well as ensuring all tests are as per the registered specifications.  If there are any corrections to be made, the documents are returned to the Stability Team Leader or Designee for correction.  Once all corrections are complete the Laboratory Manager or designee will sign the protocol and reports.  Approved protocols and reports are filed in the corresponding stability folder in the designated location in the laboratory.

5.4.4 A photocopy of the release testing results must be filed in the stability product folder.

5.4.5 If the Registration Specification is updated a documented evaluation will be made by

the Stability Team Leader in consultation with the QA Manager as to whether or not to update the stability protocols and reports.

5.5 Labelling and Storage

5.5.1    Upon approval of the Stability Protocol and Reports the Stability Team Leader or designee will generate sample labels for each corresponding condition / time point.

The stability sample labels should contain but are not limited to the following details:

Product Name

Protocol Number

Lot Number

Storage Condition

Time point

Date In (study commencement date)

Due Date (for testing)

Actual Pull date

5.5.2 The labels will be printed and compared against the approved protocol for correctness.  If any errors are found the original labels must be destroyed.  The appropriate corrections must be made and new labels must be printed.

5.5.3 The samples are divided up so as to ensure adequate samples for each timepoint and the labels are attached to the corresponding sample.

5.5.4 The labeled stability samples are stored in the specified stability chamber on the study commencement date specified in the Protocol. The stability samples should be stored in the chamber in month order.

5.5.5 A control sample must be stored at 4°C.  This sample is used as a control sample when required.

5.5.6 All products should be stored in the following stability storage conditions:

5.5.6.1 For Example: Products are exported to the Asean markets should be stored at 30°C/75%RH with a backup sample to be stored at 30°C/65%RH.

5.5.6.2 For Example: Products for the non- Asean markets should be stored at 30°C/65%RH.

5.5.6.3 Products with a labelled storage of 25°C can be stored at 25°C/60%RH.

5.5.7 All liquid products are to be stored in such a manner as to ensure that the product is in contact with all parts of the packaging (i.e. inverted or horizontal).  Extra samples should be taken for this purpose and analysed at annual test points and at the end of each storage condition.

5.6 Pulling Stability Samples from the Stability Chamber

5.6.1 The Stability Team Leader or designee must prepare a list of all stability samples due for testing at the beginning of each month, print the list out and file it in the Monthly Stability Schedule folder.

5.6.2 Pull windows are defined as the following:

Due date ± 4 days for samples with storage < 3 months Due date ± 7 days for samples with storage = 3 months

5.6.3 The Stability Team Leader or designee must pull the sample due for testing from the stability chamber within the pull window; record the actual pull date on the label of the sample and in the stability database.  Pulled samples are then stored in the designated cabinet prior to testing with exception of controlled products.

5.6.4 The stability chambers must be checked on a monthly basis to ensure all samples for that month and year have been pulled.  This check is documented on Form 740 Monthly Check of Stability Samples Stored in Ovens.

The form must be printed out each month for each oven and filed in a designated location in the laboratory.  The check must be completed within the first 14 days of each month.  If samples are found that have not been pulled by the required date the sample details must be recorded on the form.  The samples must be removed from the ovens immediately and the form must be approved by the QC and QA Managers.  Testing must be initiated on these samples as soon as possible once they are removed.  A DR must be raised to assess the impact of the sample not being pulled by the scheduled pull date.

5.6.5 The stability samples must be stored at conditions that do not compromise the product during the testing time (i.e. sample stored at 5°C must not be stored at 25°C during this period).

5.7 Stability Testing

5.7.1 The Stability Analyst must record the Product Name, Lot Number, Time point, Storage Condition, Due Date for Testing and Actual Pull Date of the stability sample into the laboratory workbook / QC Record prior to commencement of stability testing.

5.7.2 The Stability Analyst must conduct the stability testing according to the test methods specified in the approved protocol.

5.7.3 Chemical and Physical Testing must be completed within 30 calendar days from the actual pull date of the sample.  “Completed” is the date of acquiring the raw data (e.g. date of HPLC injection).

If testing is not completed within this time frame a DR must be raised to assess the impact of not testing the stability samples within the required time frame.

A planned DR (Deviation Report) can be used to document an action plan and impact assessment on samples that will not be tested within the required timeframe.  This can be documented on a monthly basis and can include multiple lots and products.

5.7.4 Microbiological testing must be initiated within 30 calendar days of the actual pull date.

5.7.5 The Stability Analyst must document the testing in the laboratory workbook or any other documents as required as per Good Documentation Practices.

5.7.6 The Stability Analyst must report any result, which is outside of the registration specifications or other specifications outlines in the protocol, or out of trend  (even if within specification) to the Stability Team Leader or designee.

5.7.6.1 The Stability Analyst must raise and carry out an LIR (Laboratory Investigation Report) when required in accordance with SOP LAB-055 Laboratory Results-Out of Specification Investigation.

5.7.6.2 The Stability Team Leader or designee must carry out the investigation in accordance with SOP LAB-055 Laboratory Results-Out Of Specification Investigation; notify the Laboratory Manager / Quality Authority of any confirmed out of specification results.  A DR and/or CR are initiated when required.

5.7.7 On completion of testing, the Stability Analyst must evaluate the results against the registration specification, against any other specifications outlined in the protocol and against that of previous time points.  Acceptance criteria for an out of trend result compared to a previous time point are:

For Assay: Variation from previous test point = 4%.

For Dissolution: If initial and second stage test Specifications for dissolution are not met, resulting in a third level of testing, and the product under test has no history of requiring a third level of testing, results shall be considered out of trend.

5.7.8 The Stability Analyst must enter the test results and all relevant information required into Review Page and reports(s) in the Stability Database on completion of testing.

5.7.9 The Stability Analyst should report the results with the same number of decimal places as the specification (unless specified in the reporting criteria from the method; this is normally applied to degradation products).

5.7.10 The reports must include references to any LIRs / DRs raised and a reference to the raw data.  The completed report must be printed by the analyst after each time point has been tested.  All blank spaces must be lined out.  The report must be signed and dated by the analyst in the ‘reported by’ section and forwarded to the reviewer for review along with the completed workbook / QC Record that contains the raw data.

5.7.11 The reviewer must check the stability testing laboratory workbook / QC Record and any other related documents for completeness.  If corrections need to be made the workbook / QC Record must be returned to the analyst for correction.  Once all corrections have been made the reviewer will sign off the ‘reviewed by’ section of the workbook / QC Record and proceed with the review of the reports.  All relevant information must be filled into the review page of the Stability Database on completion of the review.

5.7.12 The information in the reports must be checked against the reviewed raw data for completeness.  All relevant LIRs / DRs must be referenced on the report.  The raw data reference on the report must be checked for correctness.  The report must be checked against the approved protocol or against a previously reviewed report.  If any corrections are needed the report must be returned to the analyst for correction.  Once all corrections are addressed the reviewer must sign the report in the ‘Reviewed By’ section.  Reviewed reports are stored in the product folder in the designated location in the laboratory.

5.7.13 Any left over samples should be stored until review is complete before being disposed off.

5.7.14 Upon completion of the last time point testing of a study, the Stability Team Leader or designee should review the entire study for completeness and write up a summary report for the study.

5.8 Termination of Stability Study

Termination of a stability study must be documented by the Stability Team Leader or designee, assessed and approved by the Laboratory Manager and QA Department.