1. Purpose
The intent of this procedure is to provide the Active Pharmaceutical Ingredient (API) Manufacturing Sites with the principles of a stability program.
2. Scope and Applicability
This procedure is applicable to all sites manufacturing active pharmaceutical ingredients.
This procedure applies to all active pharmaceutical ingredients. The protocols cover the following categories:
(1) New commercial active pharmaceutical ingredient – first three, or early, full-scale batches manufactured at the commercial manufacturing site.
(2) Annual Maintenance Stability testing
(3) Stability testing associated with process modifications
(4) Stability testing associated with process validation and process deviations Stability studies conducted as described in the procedure will conform to worldwide registration and QA/GMP/ICH/WHO requirements.
3. Definitions
3.1 Lead Team/Site
Is the Team/ site that is accountable for conducting specified QA activities, notably QC analysis, release and Stability studies, as recorded in the QA agreement between the Lead Site and the Receiving Site.
3.2 Commercial Stability Team/Site
Refers to the site that either conducts the stability studies on a product(s) or Active Pharmaceutical Ingredient (API)or is responsible for managing studies at a specified contractor. When a Commercial Stability Team/Site allocates all or part of a stability study to another site or contactor the work will be managed by the Commercial Stability Site. The Lead Site and Commercial Stability Site may be the same.
3.3 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 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.
3.4 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.
3.5 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.
3.6 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.
3.7 Secondary Package
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.
3.8 Stability
The capacity of a drug product or API to remain, over time, within specifications established to ensure quality.
3.9 Manufacturing Change Management Process
This is the process that facilitates the tracking, review and approval/rejection of changes that may impact on the registered data and on the international supply of products.
3.10 Trend Analysis
A non-statistical approach to evaluate stability data tendencies over time utilizing techniques such as scatter plots, visual examination, etc. It is intended to detect stability trends that may be indicative of changes in process, methodology or any other parameters that might affect the chemical/physical parameters of the active pharmaceutical ingredient.
3.11 Statistical Analysis
Analysis using formal statistical techniques, e.g. regression analysis, to objectively analyses and compare data.
3.12 Re-test Date
The date when samples of the active pharmaceutical ingredient shall be re- examined to ensure that the drug is still suitable for use.
3.13 Re-test Period
The period of time during which the active pharmaceutical ingredient can be considered to remain within specifications and therefore acceptable for use in the manufacture of a given drug product, provided that it has been stored under the defined conditions; after this period, the batch shall be re-tested for compliance with specifications and then used within a previously defined time period.
4. Responsibilities
4.1 It is the responsibility of each Operation Site to establish stability testing procedures that are consistent with the requirements of this Q&C Procedure and to follow these procedures when conducting stability studies assigned to the site in the Stability Master Plan (SMP).
4.2 It is the responsibility of each Commercial Stability Site to conduct individual stability studies according to the relevant `Integrated Stability Protocols` or local protocols if no `Integrated Stability Protocol` has been issued.
5. Guideline
In case of discrepancies, the regulatory filing/commitments supersede the clauses contained in this Q&C Procedure.
5.1 Introduction
Ongoing surveillance of the stability profiles of commercially available active pharmaceutical ingredients is an integral part of the Company’s quality assurance program. It is essential that stability studies are conducted at Stability Sites as detailed in the SMP issued by the Dossier Management Group (DMG). It is recognized that minor variations may be required as a result of special requirements by national authorities. In these cases the deviations shall be embodied within the stability study protocols, and noted in the SMP.
5.2 Active Pharmaceutical Ingredient – New Product Introduction
5.2.1 Selection of Batches/Packs
Samples of three distinct batches from the first commercial manufacturing campaign, from each manufacturing site, shall be placed into the stability program. Each of the three batches set down shall be in a miniaturized replica of the actual packaging used for storage and distribution, including the closure system and any desiccants e.g. solid drug substance in polyethylene liners and liquid drug substance in glass.
5.2.2 Testing Schedules
Note 1
Initial results may be taken as the results of the batch release testing only when:
– study set down date is within 30 days from release testing.
– the release methods are identical to those used for stability studies, e.g. assay.
Where the 30-day time limit is exceeded or differences exist between release methods and stability methods, re-analysis by the stability methods shall be conducted at set down.
L = Long Term Stability
25°C/60%RH = Long term storage condition, general case according to ICH to support marketing in Climatic Zones I and II as defined in USP.
30°C/65%RH = Long-term storage condition, according to ICH to support marketing in Climatic Zones III and IV. 30°C/65%RH can be used instead of 25°C/60%RH as the long-term condition for Zone I and II.
Note 2
40°C/75%RH = Accelerated storage condition as defined in ICH. Accelerated studies on production scale batches are not required in ICH guideline for a new drug substance, but may have been included in a commitment.
Note 3 30oC/65%RH = Intermediate condition to replace 40oC/75% RH where allowed by ICH Guidelines. The above protocol is geared to meet general ICH requirements and requirements for importation from zone III and IV climate zone countries, but may be modified depending on specific active pharmaceutical ingredient characteristics.
For example, if it is known from earlier studies that the active pharmaceutical ingredient will not remain in specification when stored for more than 36 months at the recommended storage condition, then the duration of long term studies can be reduced to 36 months.
The protocol should be the same as that for the primary batches unless otherwise scientifically justified.
5.2.4 General Requirements for Studies on New Commercial APIs
5.2.4.1 Temperatures shall be controlled to±2°C and relative humidity at±5%RH. Excursions exceeding these ranges for more than 24 hours shall be recorded and evaluated and their impact assessed and documented.
5.2.4.2 Samples shall be taken according to approved sampling plan.
5.2.4.3 When samples are taken off test, they shall be stored within the labelled storage conditions and analysis completed within 30 calendar days.
5.2.4.4 The maximum time between the final processing stage (include particle size reduction where this is carried out) of the batch manufacture and stability set down is 60 calendar days.
5.2.5 Data Generation and Analysis
5.2.5.1 All analytical and microbiological tests shall be fully validated in accordance with ICH requirements (ICH Q2) and the assay for active pharmaceutical ingredient purity must be stability indicating.
5.2.5.2 Testing shall be performed in singlicate where method precision allows and where not prohibited by local regulatory authorities.
5.2.5.3 Documented procedures shall be used to investigate adverse trends and/or ‘out-of-specification’ results and report any confirmed out-of-specification results to local senior QA management.
5.2.5.4 The Commercial Stability Site shall provide data to DMG in the agreed format and to an agreed time schedule.
5.2.5.5 Record all valid results. This will normally be only one, but if more than one determination is carried out, record each result, and compare each result with the specification. Act on any individual, confirmed `out-of-specification` result.
5.2.5.6 The use of ‘trend analysis’ is required annually. Statistical analysis is not a routine requirement, but may be useful in situations where the data is not conforming to expectations, e.g. comparison with historical data.
5.2.5.7 When required, transfer of test methods to a site shall be subject of an analytical and/or microbiological technology transfer from R&D, (new products) or from another commercial manufacturing site (established/mature API:s).
5.3 Active Pharmaceutical Ingredient – Annual Maintenance Stability Protocols
5.3.1 Selection of Batches/Packs One batch of each active pharmaceutical ingredient manufactured at each site shall be placed on stability annually, together with any additional studies detailed in the SMP. Each batch shall be set down in a miniaturized replica of the actual packaging used for storage and distribution, including the closure system and any desiccants e.g. solid drug substance in polyethylene liners and liquid drug substance in glass.
5.3.2 Testing Schedule The schedule below prescribes a varied pull schedule for annual maintenance stability testing dependent on the retest period of the active pharmaceutical ingredient, ranging from 18 to 60 months.
Note 1Initial results may be taken as the results of the batch release testing only when:
– release testing is completed within 60 days of the study set down date and
– the release methods are identical to those used for stability studies, e.g. assay.
Where the 60-day time limit is exceeded or differences exist between release methods and stability methods, re-analysis by the stability methods shall be conducted at set down.
L = Long Term Stability 25°C/60%RH = Long term storage condition climate I and II, according to ICH 30°C/65%RH = Long term storage condition climate zone III and IV according to ICH The actual protocol conditions may differ depending on the API characteristics and these conditions will be established based upon the protocol developed to support the first three production batches.
Additionally, regulatory commitments may supersede the recommended protocol structure as presented above.
5.3.3 General Requirements for Annual Maintenance Studies on APIs
The general requirements for studies on new APIs (see Section 5.2.4) shall apply to annual maintenance studies, except that the requirement to repeat the initial analysis if set down occurs more than 30 days after release testing is relaxed to 60 days providing that the first sample pull is 12 months or later.
5.3.4 Data Generation and Analysis – See Section 5.2.5
The general requirements for studies on new APIs (see Section 5.2.5) shall apply to annual maintenance studies.
5.4 Post-Marketing Approval Changes
Where a process has been modified, additional samples shall be retained and placed into the commercial stability program. The test protocol and number of batches shall be dependent upon the magnitude of the change and local regulatory requirements. During the MCM process, Regulatory, Operations QA, and possibly R&D, will determine what stability studies are mandated to support the change. Additionally, locally managed changes could require the initiation of stability studies. The following modifications are typical of situations, which will require additional stability studies:
– Change in manufacturing process of the active pharmaceutical ingredient
– Change in manufacturing site and/or manufacturer of the active pharmaceutical ingredient
– Change in the batch size of the active pharmaceutical ingredient
Note: Changes to an active pharmaceutical ingredient may require additional stability studies on formulated products incorporating the active pharmaceutical ingredient.
5.5 Validation Studies and Process Deviations
The need for studies to be conducted in support of manufacturing process validation studies or to support the release of batches that have been subject to a ‘deviation’ during processing shall be decided by the QA Management of the processing site, in consultation with the QA Management of downstream manufacturing (formulation) sites who may receive the batches for processing. The study conditions and testing schedules given in Sections 5.2.2 and Section 5.3.2 shall be used by the QA Management as a reference point when deciding on the protocols for these studies.