1. Purpose
The purpose of this procedure is to describe how stability studies carried out at contractors shall be managed.
2. Scope and Applicability
All stability studies on commercial products that are conducted by contract manufacturers or contract laboratories.
3. Definitions
3.1 Stability Master Plan (SMP)
A plan that details the stability studies required to maintain compliance with company’s regulatory and GMP obligations and commitments and assigns each study to a specific Commercial Stability Site.
3.2 Stability Protocol
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 an Active Pharmaceutical Ingredient (API) in a single specified market. It should include time points and conditions employed, and methodology used to generate stability data.
3.3 Integrated Stability Protocol
An integrated stability protocol is a detailed plan used to generate and analyze stability data in support of the retest period of an Active Pharmaceutical Ingredient (API) 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 API and/or the requirements of more than one market in a single plan/document.
3.4 Lead Team/Site
Refers to the team/site that is accountable for conducting specified Quality Assurance activities as recorded in the quality assurance contract (agreement) between the sponsor and the contractor.
3.5 Quality Agreement Co-ordination (QAAC) Team/Site
The team/site assigned by Supply & Capability (S&C) to co-ordinate Good Manufacturing Practice, GMP related interactions and issues between an established contractor and sponsor when the contractor supplies products assigned to more than one Lead Site or is geographically and/or culturally remote from the assigned Lead Site.
3.6 Bulk Package
The package used to store and/or transport an API or drug product such as tablets. For API and solid dosage forms, this is usually a drum double-lined with polyethylene. Some components of a bulk package fall within the definition of a ‘primary package’ since they are in direct contact with the product.
3.7 Primary Package
Any material employed in the packaging of a pharmaceutical product or active pharmaceutical ingredient. Primary packaging material(s) form the container/closure system for the product and therefore may be in direct contact with the product. Examples include HDPE bottles/caps, blister strip packs, tubes/caps for ointments, syringes, Turbuhaler or plastic bag.
For the purposes of commercial stability studies, the primary package, i.e. the container closure system, shall be considered to be independent of any differences in labeling and/or printing attached to, or on, the primary package, providing that appropriate product/container/label interactions have been conducted on all such variants.
3.8 Secondary Packaging
Secondary packages are not in direct contact with the product or active pharmaceutical ingredient. Examples include, cartons used to contain blister packs, fibreboard drums for plastic bags, cartons for tubes. Secondary packaging components essential to the function or stability of the product, although not in direct contact with the product, should be regarded as primary materials or components.
Examples include blister packages of single dose pipettes (needed for stability), ampoules stated to be sterile on the outside, needle covers of syringes, inks for printing on primary plastic containers, capping for stoppers, desiccant sachets, etc.
4. Responsibilities
Quality Assurance Agreement Co-ordination (QAAC) Team/Site/ Lead Team/Site
4.1 It is the responsibility of the assigned Lead team/Site (or Quality Assurance Agreement Co-ordination (QAAC) Site if one is assigned) to have a written QA Agreement with the contractor that clearly identifies the need, if any, for the contractor to perform stability studies.
4.2 It is the responsibility of the Lead team/site to agree with the contractor a Stability Master Plan and stability study protocol (or Integrated Stability Protocol) that have been approved through company business processes.
4.3 It is the responsibility of the Lead team/site to transfer to the contractor the test methodology identified in the stability protocol.
4.4 Where necessary, e.g. when stability studies are assigned to contract laboratories, it is the responsibility of the Lead team/site (or another Site if agreed by the Lead Site) to provide to the contractor appropriate quantities of stability study batches. It is the responsibility of the Lead team/site to link the contractor activities with Company’s QA processes, e.g.
– Change Management.
– Management of Stability Master Plans and protocols.
– OOS reporting and Issue Management.
– Data reporting
Contractor
4.6 It is the responsibility of the contractor to conduct studies according to the study plan and protocol agreed with the sponsor company and in compliance with cGMP codes relevant to the markets being supplied.
4.7 It is the responsibility of the contractor to carry out a laboratory investigation into any ‘Out of Specification’ (OOS) results, or adverse trend likely to lead to an OOS result within or at the shelf life of the product, to confirm, or otherwise, their validity and to report confirmed OOS results, and/or adverse trend likely to lead to an OOS result within or at the shelf life of the product, to the Lead team/site within 3 working days (within 1 working day for products marketed in USA).
4.8 It is the responsibility of the contractor to report all data from ongoing studies to the Lead team/site at least annually or more frequently if required by the Lead Site.
5. Procedure
5.1 QA Agreement
The Lead Team/Site (or Quality Assurance Agreement Co-ordination Team/Site if one is assigned) shall develop a QA Agreement with the contractor that identifies the need, if any, for the contractor to conduct stability studies on material made by the contractor, or in the case of contract laboratories, on study batches provided by the sponsor.
5.2 Stability Plan and Stability Protocol
The Lead team/site shall arrange for a stability plan and stability protocol to be produced and approved through sponsor’s business processes and agree these with the contractor.
5.3 Technology Transfer
The Lead team/site will transfer the technology identified in the stability protocol to the contractor (normally confined to test methodology).
5.4 Study Batches
5.4.1 Products made at the Contractor The contractor shall select bulk, primary or secondary packaged samples (as required by the study protocol), typical of its manufacture, for stability studies. Study batches should be less than 6 months old when stability studies are initiated. If a contract manufacturer/packager is not required to perform stability studies it shall provide samples for stability studies to sponsor when requested to do so by the Lead team/site.
5.4.2 Products supplied by sponsor When the contractor is a contract laboratory the sponsor Lead team/site (or another agreed Site if agreed by the Lead team/site), shall provide appropriate quantities of study batches to the contractor.
5.5 Study Conduct and Reporting
The contractor shall conduct the stability studies described in the study plan using the protocol agreed with the sponsor. Laboratory work shall comply with cGMP codes relevant to the markets being supplied. OOS results, or adverse trend likely to lead to an OOS result within or at the shelf life of the product, shall be investigated immediately after they occur.
The contractor shall report any confirmed OOS results and/or adverse trend likely to lead to an OOS result within or at the shelf life of the product to the Lead Site within 3 working days of confirmation (within1 working day for products marketed in the USA). The contractor shall report all results from studies to the Lead team/site annually or more frequently if requested by the Lead Site. Results should be reported in a format/detail compatible with data reporting procedure.
5.6 Linkage to sponsor’s Q A processes
The Lead team/site shall provide the link between the contractor and sponsor’s QA processes in the same way that it does for stability studies conducted at the Lead team/site. These include:
– Change Management.
– Study plans and protocols.
– OOS/Adverse Trend reporting.
– Stability data reporting