1. Purpose
The purpose of this document is to describe the procedure for the preparation and management of Stability Protocols and Stability Master Plans for marketed products and Drug Substances.
2. Scope and Applicability
This Procedure is applicable to all plans and protocols for stability studies on commercial products and Drug Substances.
3. Definitions
3.1 Commercial Stability
Site Refers to the manufacturing Site that either conducts the stability studies on a product(s) or Drug Substance or is responsible for managing studies at a specified contractor. When a Commercial Stability Site allocates all or part of a stability study to another manufacturing Site or a contractor the work will be managed by the Commercial Stability Site. The Lead Site and the Commercial Site may be the same.
3.2 Commercial Packaging
Site Refers to the Site at which manufactured product is packaged in the primary marketed sales package.
3.3 Stability Master Plan (SMP)
A plan that details the stability studies required to maintain compliance with regulatory and GMP obligations and commitments and assigns each study to a specific Commercial Stability Site.
3.4 Stability Protocols
A Stability Protocol is a detailed plan used to generate and analyze stability data in support of the shelf (expiry) life of a Drug Product or retest period of a Drug Substance in a single specified market. It should include time points and conditions employed, and methodology used to generate stability data.
3.5 Integrated Stability Protocols
A detailed plan used to generate and analyze stability data in support of the retest period of a Drug Substance or the shelf (expiry) life of a Drug Product. It should whenever possible incorporate the stability requirements of more than one Drug Product containing the same Drug Substanceand/or the requirements of more than one market in a single plan/document.
3.6 Manufacturing Formulation Number (MF) or Article Number (Art. No.)
The unique Manufacturing or Master Formulation number assigned to this Formulated Drug.
3.7 Pack Code
A unique code assigned to a primary package used at a particular packaging site, based on the chemical and physical make up of the components of the primary package.
3.8 Special Study
A stability study in addition to those required by the International Conference on Harmonization (ICH) and the Annual Maintenance Program. Examples may include, but are not limited to, batches involved with validation studies, process deviations and manufacturing changes (including changes in packaging).
3.9 Set Down Limits
The Set Down Limits shall be the tightest registered release limits for each test parameter in any market, in order that studies will satisfy all regulatory submissions.
3.10 Out of Specification (OOS) Reporting Limits Out of Specification (OOS)
Reporting Limits shall be the tightest registered lifetime limits for each test parameter in order that studies with no reported OOS will satisfy all regulatory submissions.
3.11 Market Reporting Group
A group of markets that share the same or equivalent primary packaged product and same test schedules.
3.12 Pack Evaluation Team (PET)
A team comprised of members drawn from Operations set up to assign Pack Codes for primary packages and to evaluate their equivalency in stability terms on a product basis.
3.13 Matrixing
The statistical design of a stability protocol such that only a fraction of the total number of samples are tested at any specified point in time. The tested samples for the same product should cover e.g. different batches, different strengths, different sizes of the same container and closure. (See ICH Q1D Bracketing and matrixing designs for stability testing of drug substance and drug products.)
3.14 Bracketing
The design of a stability protocol such that at any point in time only the samples on the extremes are tested, e.g. to evaluate a range of primary package sizes. (See ICH Q1D Bracketing and matrixing designs for stability testing of drug substance and drug products.)
4. Responsibilities
4.1 Registration Officers ROs
The Registration Officer in the Dossier Management Group is responsible for creating and maintaining Stability Protocols and Stability Master Plans for the marketed products and Drug Substances in consultation with the Stability Manager.
4.2 Commercial Site Stability Manager
The Commercial Site Stability Manager or person nominated by the Stability Manager is responsible for
– creating and maintaining protocols that are required for studies that are a result of process validation or process deviations.
– approving Stability Protocols created by DMG ROs
– assuring adequate facilities and resources to execute studies according to the SMP at their site
– acting as the primary contact for the flow of samples and information between international sourcing sites
– ensuring stability set downs according to plans and protocols
4.3 Pack Evaluation Team
The DMG ROs responsible for coordinating Pack Codes and Pack Equivalency Reports (PER) within the Pack Evaluation Team are responsible for supplying other DMG ROs with the relevant information for their Drug Products or Drug Substances.
5. Guideline
5.1 Introduction
The DMG RO in consultation with the Stability Manager or person nominated by the Stability Manager from the Commercial Stability Site shall create the Stability Protocol and Stability Master Plan. The protocol shall be based upon the ICH Stability Guidelines for new products, WHO Guidelines for stability testing of pharmaceutical products containing well established drug substances in conventional dosage forms and other local guidelines that may be relevant to specific studies.
The Stability Protocol shall include the first or early commercial batches and/or the Annual Maintenance stability protocols. These protocols may be used for special studies when they exactly match the special study requirements.
For new products it may be sufficient to only cover the ICH batches in the first version of the protocol. The first versions shall be reviewed to include Annual Maintenance protocols prior to Annual Maintenance studies being initiated.
If there are regulatory commitments, they may supersede the recommended ICH stability guidelines. Where different formulation types exist (for example: creams and transdermal patches), separate Integrated Protocols or Protocols should be considered.
If bracketing or matrixing is considered, the ICH Guidelines “Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products” shall be used as guidance. The Stability Master Plan provides a five years forward visibility of the commercial stability set down program by detailing scheduled new studies as well as active studies. Additional special studies shall be added to the SMP when the need for the studies is identified.
5.2 Information to be included in a Stability Protocol
5.2.1 Purpose and Scope
This section of the protocol states the products involved in the protocol.
5.2.2 Sites involved in Studies
This section shall identify the Bulk Drug Site, the Formulating Site, all of the concerned Packaging Sites, the Commercial Stability Site, the site where the stability samples are stored and the Testing Site(s).
Note: In some cases the initial results may have been generated by the site performing the release testing.
5.2.3 Study Summary
The Study Summary provides Composition Codes (the Manufacturing Formulation Numbers or Article Numbers)
– their associated Pack Codes
– Market Reporting Group.
– conditions for set down
– each Manufacturing Formulation /Pack Code study length in tabular form
– type of Study e.g. Annual Maintenance
The Study Summary therefore represents what each marketed product’s study length is in its primary pack and the conditions needed for stability to support the shelf (expiry) life.
5.2.4 Schedules
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.
– mature formulated products that contain only an Annual Maintenance stability schedule
– Drug Substances
A stability schedule shall contain the initial and all test points in months for each condition that is applicable for the various Climatic Zones (I-IV), which the studies support.
A table with the time points and required tests (as identified in the Registered Tests section) shall be constructed for each condition and market reporting group. The schedule conditions, time points, and tests shall be based upon The stability protocols agreed with the various regulatory agencies for the early commercial batches and Annual Maintenance batches.
An example of a schedule for the three early commercial batches marketed only in Climatic Zones I and II is given below:
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 providing that the first sample pull is 12 months or later) proceeding the start of the study and the release methods are identical to those used for stability studies.
Where differences exist between release methods and stability methods, re- analysis by the stability methods shall be conducted at set down. The stability schedule shall designate the study length. For new formulated products the initial shelf (expiry) life will generally be less than the maximum expiry life of 48 months.
For new formulated products the stability schedule shall indicate that the required study length is a maximum of 48 months.
5.2.5 Registered Tests and Specifications
All tests required for stability shall be presented with their associated Registered Release Limits and Registered Lifetime Limits. The Registered Lifetime Limits shall specify exactly what the limits are. The Registered Release Limits shall specify ‘As lifetime’, if they are identical to the Registered Lifetime Limits, if not the Registered Release Limits shall be specified exactly.
For tests that have different limits for different markets, those limits shall be listed by country. The release and lifetime limits, and methodology used for stability testing shall be included or referenced in the stability protocol and be consistent with the regulatory approved documentation. The stability site reference numbers applicable to methods and limits may be listed. This listing is optional.
5.2.6 Integrated Specifications
An Integrated Specification shall contain all registered tests required for stability studies, together with their associated Set Down Limits and OOS Reporting Limits The OOS Reporting Limits shall be the tightest registered lifetime limit for each test parameter for any market in order that studies will satisfy all regulatory submissions.
The Set Down Limits shall be the release limits, if registered. If they are not registered, the Set Down Limits shall be the Registered Lifetime Limits and shall specify ‘As lifetime’ if they are identical to the OOS Reporting Limits.
Where differences occur the limits should be specified exactly. A table shall be created for each market reporting group.
5.2.7 Non registered tests and specifications
A table entitled “Non registered tests and specifications” shall be created for tests (and associated limits) conducted during stability studies but that do not appear in the registered specification, e.g. “Appearance of primary packaging”. For consistency the headings in the table shall be the same as in 5.2.6 (Integrated Specifications) i.e Set Down Limits and OOS Reporting Limits.
5.2.8 Sample Plans
A specific quantity of tablets, liquid or units is required to complete testing for each Stability Protocol. For each Manufacturing Formulation Number/Article Number and Pack Code combination the number of tablets, quantity of liquid or unit per study and the number of primary packs per study shall be listed. The specific quantity of tablets, liquid or units shall include overages for OOS testing and microbiological testing as required. 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.
5.2.9 Justification of Stability Protocols
Derivation of the Integrated Specifications – An explanation for the derivation of the integrated specifications shall be provided where applicable.
For example, various markets require broader release and lifetime specifications for the active agent content of a product than other markets, dissolution tests and their associated specifications require different compendial requirements (USP vs Ph. Eur. vs BP) and microbiological purity of oral dosage forms is a Ph. Eur requirement only.
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 labeled storage conditions.
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.
Time points – A justification shall be provided for the choice of the time points. For example, reference shall be made to the ICH guidelines or as specified in regulatory submissions.
Test Parameters – A justification shall be provided for the inclusion and/or exclusion of particular test parameters from the protocols. Bracketing and matrixing – In case of making use of bracketing and matrixing a justification shall be provided.
5.2.10 Document Change History
All changes that have been done at revision of the Protocol shall be listed under this section.
5.2.11 Revision of the Stability Protocol
If the Stability Protocol has had no revisions after two (2) years from the last signature (issue date) of the approved protocol, the DMG RO in consultation with the Stability Manager shall initiate a review of the protocol. The following changes shall result in the creation of a new version of the Stability Protocol.
– Change in specification
– Change in the tests applied for example a test added or removed
– Condition change
– A new pack code added or an existing pack code removed
– Change in pull times
– A market reporting group is added or removed
– Change in Commercial Stability Site/Testing Site
The first and subsequent versions of the Stability Protocol shall be reviewed by all those required to approve the protocol.
5.3 Information to be included in a Stability Master Plan
In the SMP the DMG RO shall identify the studies required to meet regulatory requirements and GMP compliance and decide upon sample rotation among packaging sites.
5.3.1 Creating the SMP
To create the plan the following information which is contained in the protocol is needed:
– Identification of Drug Product or Drug Substance
– Market Reporting Group
– Study type
Formulation site. (For liquid products the formulation site is the same as the packaging site)
– Drug Substance Site
– Packaging Site and Pack Details
– Composition code
– Length of study
– Protocol conditions
5.3.2 Studies to put in the SMP
– The first three commercial batches
– Annual Maintenance
– All Special Studies.
5.3.3 Information needed to decide on sample rotation
Sample rotations are only applicable to solid dosage forms originating from packaging sites supplying ROW. The Pack Equivalency information contained in the Pack Equivalency Report (PER) is required for deciding sample rotations among packaging sites.
Rotation can only be applied for equivalent packages, allowing sampling for stability testing to be done from different sites every year for a period of five years. This means that if there are more than five packaging sites for the product, samples must be taken from more than one site every year.
Note: Stability studies to support products marketed in the US must be package site specific and must not be included in rotations involving sites supplying the ROW.
5.3.4 Revision of the SMP
SMPs shall be brought up to date by 1st of November each year to facilitate sample requests from Commercial Stability Sites to Packing Sites.