LAB-070 Preparation and Maintenance of Stability Protocols for pharmaceuticals Products

1. Introduction

1.1. The Stability protocol or Integrated Stability Protocol is a detailed plan used to generate and evaluate stability data in support of the expiry life.  This protocol includes Manufacturing Formulation (MF), test points, conditions, an Integrated Stability Specification, and methodology used for the generation of stability data, or reference to where the methodology is described.  Where different formulation types exist, separate Integrated Protocols or protocols should be considered.

1.2. Stability Manager from the Commercial Stability Site shall create the Integrated Stability Protocol in consultation with management team.

1.3. The Integrated Stability Protocol shall include the three early commercial batches and the annual maintenance stability protocols.

1.4. The Integrated Stability Protocol shall be written and signed by Technical Service staff and approved by the Stability Manager from the Commercial Stability Site.

1.5. Separate Integrated Stability Protocols for Special Studies, (excluding process DR and studies to support process validation) shall be generated by the Technical Service staff working on the product registration, in consultation with the Stability Manager from the Commercial Stability Site as these studies become necessary.

1.6. The Stability Manager shall initiate a new version of the Integrated Stability Protocol, when appropriate changes such as new pack/concentration sizes have been added to the product line or specifications have been changed/added.  However, it is not necessary to create a new version of the integrated protocol if the modules are updated as a result of minor changes, i.e., additional stability data added to the stability module for regulatory use.  If the Integrated Stability Protocol has had no revisions after two (2) years from the last signature (issue date) of the approved protocol, the Stability Manager shall initiate a review of the protocol to determine if revisions are required.  A new version of the protocol shall be issued with appropriate changes or be issued even if the review dictates no changes.  The Integrated Stability Protocols for special studies do not require an automatic review every two years, however they should be reviewed and re‑issued if they are to be re‑used more than 2 years from their previous approval date.

1.7. In the case of studies to support process DR and process validation, the Stability Manager, in consultation with the technical service and local QA Management, shall initiate new protocols for studies that are required because of process DR or process validation programs.  It may not be necessary to create a new integrated protocol for each new study set down because of a process DR if an existing integrated protocol meets the requirements of the new study.  As with other integrated stability protocols, the release and stability limits, and methodology used in stability testing should be referenced (see sec. 2).

2. Information to be included in an Integrated Stability Protocol

2.1. Site for Study

This section shall identify the Commercial Stability Site, where the stability samples are stored, the testing site(s) and the site(s) that produce the initial results.

2.2.  Study Summary

The Study Summary provides the Manufacturing Formulation numbers, their associated Pack Codes, conditions for set down, and each Manufacturing Formulation /Pack Code study length in tabular form.  The table, therefore, represents what each marketed product’s study length is in its primary pack and the conditions needed for stability to support the expiry life.  A statement shall be included in the Study Summary, if secondary packaging is required for stability set downs for products that are, for example, light sensitive.  The study length (months) is listed in the conditions columns.  The following table can be used as a guide.

*This condition is a minimum condition; a higher relative humidity condition may be utilised such as 30°C + 2°C/ 80% RH + 5%.

2.3. Schedules

2.3.1.  A stability schedule shall be available for new formulated products that include a schedule for the three early commercial batches and for annual maintenance stability.  A stability schedule shall be available for mature formulated products that contain an annual maintenance stability schedule.

2.3.2. A stability schedule for the three early commercial batches shall contain the initial and all test points in months for each condition that is applicable for the various Climatic Zones, which the studies support.  A two dimensional table with the time pulls and required tests (as identified in the Registered Tests section) shall be constructed for each condition and market. The tables shall be constructed in such a way that the testing required at each time point is clearly identified. The schedule conditions, pull times, and tests shall be based upon the Development batch stability protocol submitted to the various regulatory agencies in order to comply with the ICH stability guidelines for new formulated products.  Regulatory commitments may supersede the recommended ICH stability guidelines.  Therefore, the stability schedule may vary from the ICH stability guidelines.   An example is given below:

2.3.3. A stability schedule for annual maintenance stability batches shall contain the initial and all test points in months for the conditions that are applicable for the various Climatic Zones that the studies support.  A two dimensional table with the time pulls and required tests (as identified in the Registered Tests section) shall be constructed for each condition and market. The tables shall be constructed in such a way that the testing required at each time point is clearly identified.  The schedule conditions, pull times, and tests shall be based upon SOP LAB-075.  Regulatory commitments may supersede the guidelines and examples recommended in SOP LAB-075. Therefore, the stability schedule may vary from these guidelines. An example is given below:

2.3.4. Note that fewer or more time points may be required depending on the regulatory requirements.

2.3.5. A note, which references the initial test point, shall be included.  The note shall state that initial results may be taken as the results of the batch release testing only when the results are obtained within the 30 days (60 days for annual studies) proceeding the start of the study and the release methods are identical to those used for stability studies, e.g., assay.  Where differences exist between release methods and stability methods, re-analysis by the stability methods shall be conducted at set down.

2.3.6. The stability schedule shall designate the study length ‑ however, for new formulated products the initial expiry life will generally be less than the maximum expiry life of 48 months.  Therefore, for new formulated products the stability schedule shall indicate that the required study length is extended to a maximum of 48 months.  When sufficient stability data are obtained to justify a change in expiry life for new formulated products, the Stability Manager shall inform Supply Manager and Regulatory Affairs.  An appropriate stability report will be prepared by the stability manager responsible for the product and be submitted to the appropriate markets through Regulatory Affairs.  If the final approved expiry life of the product is less than 48 months, the Integrated Stability Protocol shall be revised by the stability manager to limit future studies to the maximum expiry life obtained.  Similarly, the Integrated Stability Protocol shall be revised to reflect other changes that may take place during the product life cycle.

2.4. Registered Tests and Specifications

2.4.1. All tests required for release and stability shall be presented with their associated Release Limits and Registered Lifetime Limits.  The Registered Lifetime Limits shall specify exactly what the limits are.  The Release Limits shall specify ‘As lifetime’, if they are identical to the Registered Lifetime Limits.  If the Release Limits differ from the Registered Lifetime Limits, then the Release Limits shall be specified exactly.

2.4.2. For tests that have different Registered Release Limits and Registered Lifetime Limits for different markets, those limits shall be listed by country.  The release and stability limits, and methodology used for stability testing shall be obtained from the regulatory approved documentation. These regulatory approved documents for the release and stability Emits shall be listed on the initial version of the Integrated Stability Protocol.  If any of these documents are updated with major changes such as specification or method changes, the integrated protocol should be amended to reflect the new version numbers.  However, it is not necessary to create a new version of the integrated protocol if the modules are updated as a result of minor changes.

2.4.3. The stability site reference numbers applicable to methods and limits may be listed.  This listing is optional.

2.4.4. If any Release Limits and/or Registered Lifetime Limits change for a product, its Integrated Stability Protocol shall be revised and approved.

2.4.5. If any tests are added or removed or if the Set Down Limits and/or OOS Reporting Limits change for a product, its Integrated Stability Protocol shall be revised and approved.

2.5. Integrated Specifications

2.5.1. An Integrated Specification shall contain all tests required for product release and stability studies, together with their associated Set Down Limits and OOS Reporting. The tests and their associated limits shall be presented in tabular form.

2.5.2. The Set Down Limits shall be the manufacturing limits submitted at the time of registration.  Where manufacturing limits were not registered, the Set Down Limits shall be the Registered Lifetime Limits.  The Set Down Limits shall specify ‘As lifetime’, if they are identical to the OOS Reporting Limits.  If the Set Down Limits differ from the OOS Reporting Limits, then the Set Down Limits shall be specified exactly.  Where several market specific limits exist and are applicable to the particular Pack Code combinations that the Integrated Specification refers to, the Set Down Limit shall be the tightest manufacturing limit for each test parameter in order that studies will satisfy all regulatory submissions.

2.5.3. The OOS Reporting Limits are the Registered Lifetime Limits as registered in regulatory submissions.  In cases where there are several market specific specifications applicable to the particular product/pack combinations, the OOS Reporting Limits shall be the tightest lifetime limit for each test parameter in order that studies will satisfy all regulatory submissions.  These limits shall be met to satisfy the expiry life of each product/pack combination.

2.5.4. The Integrated Specification shall specify which tests are done on the initial sample only, initial and final test points, and at all test points.

2.5.5. If any tests are added or removed or if the Set Down Limits and/or OOS Reporting Limits change for a product, its Integrated Stability Protocol shall be revised and approved.

2.5.6. Test Parameters – a justification shall be provided for the inclusion and exclusion of particular test parameters from the protocols.

2.5.7. Derivation of the Integrated Specifications – an explanation for the Integrated Specifications for the set down and OOS reporting limits shall be provided.

2.5.8. Bulk Pack Code Containers – a simulated pack shall be utilised to reflect the drums or other containers that are actually used to store bulk Drug Substances and/or the bulk tablets for stability set downs.  The simulated pack shall be smaller than the actual drums/containers but shall be of identical or equivalent composition, (e.g., liner and fibre material).
Additional information – Additional information or justifications determined to be necessary shall be provided.  This information may relate to the selection of initial results, choice of test laboratories such as contract laboratories or appropriate information that does not suit other sections of the protocol.

2.6. Sample Plans

2.6.1. A specific quantity of units is required to complete testing for each Integrated Stability Protocol.  That is, an amount is needed for the three early commercial batches and annual maintenance stability batches.

2.6.2. For each Manufacturing Formulation Number and Pack Code combination the number of unit per study and the number of primary packs specified in strips, bottles or units per study shall be listed. The following table can be used as a guide.

2.6.3. Packs chosen for stability shall be taken in such a way, as they are representative of the entire batch.  This does not preclude taking packs from a specific portion of the packaging rim, if these are deemed to be representative of the entire batch.

2.6.4. The specific quantity of tablets, liquid or units shall include overages for OOS testing and microbiological testing as required.

2.6.5. A statement shall be included in the Sample Plans, if secondary packaging is required for stability set downs for products that are, for example, light sensitive.

2.7.  Justification of Stability Protocols

2.7.1. Study Conditions – a justification shall be provided for the choice of the long term, accelerated, and where necessary the stress conditions based on individual product properties and labelled storage conditions.

2.7.2. Sample Storage – a justification shall be provided for the specific need to store stability samples in terms of orientation (horizontal or vertical) and whether secondary packaging is necessary as for products that are, for example, light sensitive.

2.7.3. Test Points – a justification shall be provided for the choice of the test points.  For example, reference shall be made to the ICH guidelines or as specified in regulatory submissions.

2.8. Changes in the Integrated Stability Protocol

2.8.1. The Integrated Stability Protocols shall be version controlled.

2.8.2. Changes for each version of the Integrated Stability Protocols shall be listed in a section that documents what changes were made.

3. Summary of Changes