Manual – 055 Commercial Stability Testing For Formulated Products

Data from primary studies are included in first submissions for marketing approval and form the basis for an interim shelf (expiry) life for the new product. If available, data from studies on commercial scale batches may be included in the first submissions to obtain an optimum interim life for the product. Shelf (expiry) lives may be further extended as a result of later regulatory submissions containing data obtained by Operations on commercial batches. The following sections describe in detail the stability studies that will be undertaken by Operations. The use of data from the above studies to obtain and extend shelf (expiry) lives is the responsibility of company’s Regulatory Affairs (RA) and is not addressed in this document.

5.2.1 Selection of Batches/Primary Packs 

5.2.1.1 In principle, all formulations, dosage strengths and primary package variations shall be tested. A set of three distinct production scale batches of each dosage strength shall be taken from each manufacturing (formulation) site that will produce the commercial product. Each of the set of three batches shall be packaged in all primary packaging variants, i.e. different container closure systems, proposed for marketing and these primary packages shall be included in the stability program. When samples of all primary package variants cannot be obtained from the first, or early, three production batches subsequent batches shall be utilized to provide stability coverage of all package variants i.e. different container/closure systems. Where possible, dosage form batches made from at least two different lots of drug substance and key excipients shall be incorporated into the stability program.

Where bracketing is permitted by regulatory authorities in the markets affected, three batches of each dosage strength/primary package variant combination may not be required. When primary packages marketed in the USA are identical to primary packages marketed in the rest of the world (ROW), every effort shall be made to integrate the requirements of the USA with those of ROW so that the number of studies is minimized.

However, such integrated studies must be designed to meet fully the requirements of the USA with respect to supply chain specificity.

When FDA permits bracketing, three batches of each dosage strength/primary package variant combination may not be required.

When primary packages marketed in the USA are identical to primary packages marketed in the rest of the world (ROW), every effort shall be made to integrate the requirements of the USA with those of ROW so that the number of studies are minimized. However, such integrated studies must be designed to meet fully the requirements of the USA with respect to supply chain specificity.

5.2.2  Stability Protocols and Integrated Stability Protocols

A commitment to a specific stability protocol is likely to have been included in registration documents. Any differences from these commitments shall be scientifically justified and agreed with RA.

The use of matrixing or bracketing in study design shall be considered. Each study shall be referenced to the appropriate Stability Protocol or individual study protocol. Integrated Stability Protocols, or individual market specific stability protocols, shall be defined to meet the regulatory requirements of each country where the product is to be marketed. In principle, the protocols for the first, or early, three batches of a new product shall be the same as the protocols used by R&D for primary stability studies, with the following exceptions: Primary stability studies shall be conducted for a maximum period of three years at the long term storage conditions covering Climatic Zones I – IV.

Stability studies shall be conducted for a maximum period of four years at the long term storage conditions covering Climatic Zones I – IV. The duration of the above studies may be reduced if it is known from existing data that such shelf (expiry) lives cannot be justified. Whenever possible specification limits to be submitted to regulatory authorities for proposed commercial products shall be compatible with a four year shelf (expiry) life, as extrapolated from data from primary stability studies at the time of submission, provided that such limits are within generally accepted pharmacopeial boundaries, are supported by safety/efficacy studies, and are within the qualified limits for impurities as specified in ICH Q3.

Data from the stability studies on batches selected that will be used to extend shelf (expiry) lives granted (on the basis of primary data) by regulatory authorities at first approval. The following sections of this procedure summaries the general current requirements of stability studies on commercial scale batches of new formulated (drug) products. The specific conditions and time points to be used on each new product will be transferred from R&D to Operations as part of ‘Technology Transfer’ activities, and will be documented in the ‘Integrated Stability Protocol’.

5.2.3  Study Conditions and Testing Schedules (New Product Introduction)

5.2.3.1 Solid Dosage Forms

Figure

Note 1

10Initial results may be taken as the results of the batch release testing only when 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. See also Section 5.2.4.5 . 

L = Long Term Stability A = Accelerated Stability -20°C = Long term storage condition to support products that require freezing in all climatic zones as defined by ICH. 5°C = Long term storage condition to support products that require refrigeration in all climate zones as defined by ICH.

Also, accelerated conditions for product that require freezing in all climate zones as defined by ICH.

250C/60%RH = Long term storage condition to support marketing in Climatic Zones I and II and accelerated conditions for refrigerated product as defined by ICH.

For product/package combinations for the US, it may be necessary to include an additional test at a time point corresponding to the expiration date. In these cases, the need for testing at pull times greater than the expiry date should be considered. 300C/75%RH = Long term storage condition to support marketing in Climatic Zones III & IV.

The 30°C/75% RH condition is only required by a portion of the Zone IV markets, most notably Brazil and the ASEAN (Association of South East Asian Nations), but is also acceptable for markets that would accept lower humidity conditions. 400C/75%RH = Accelerated storage condition as defined by ICH.

300C/65%RH = Intermediate condition to replace 400C/75%RH where allowed by ICH Guidelines; also where the product is of a flammable nature making studies at elevated temperatures inappropriate from a safety aspect. These study conditions and testing schedules are geared to meet general ICH and tropical market requirements for products without a specific labeled storage statement or with a labeled storage statement of ‘store below 300C’.

If it is known from earlier studies that the product will not remain in specification when stored for 48 months at the long term storage conditions included in the table, the duration of long term studies can be reduced. If there is a cautionary labeling statement of ‘store below 25°C’ for a package marketed in Zones III/IV, the only long term storage condition required is 250C/60% RH.

The study conditions and testing schedules may be further modified depending on specific drug product characteristics.

For example, if the product is not sufficiently stable, physically or chemically, at 250C to justify a commercially viable shelf (expiry) life, study conditions and pull times shall be adjusted to support a viable shelf (expiry) life with a restricted labeled storage statement.

Where a lower temperature long term storage condition is used, the six month accelerated condition shall be conducted at a temperature at least 15 0 C above the designated long term storage temperature. The need to include the Ph. Eur.

Freedom from Microbiological Contamination Test in the protocol for stability studies on oral dosage products (e.g. at the beginning and end of long term study) should be considered and included in the protocol if necessary.

5.2.3.2 Liquids and Semi-solids

For products such as solutions and suspensions, contained in primary packages designed to provide a permanent barrier to water loss (impermeable), specific storage under conditions of high relative humidity is not necessary but the same range of temperatures and pull times shall be applied as for solid dosage. Liquid and semi-solid products primary packaged in semi-permeable containers (e.g. solutions in plastic bags, nose drops in small plastic containers etc.) can be sensitive to low relative humidity and consideration shall be given to appropriate testing under such conditions.

Figure

Note 1

Initial results may be taken as the results of the batch release testing only when 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. See also Section 5.2.4.5 .

L = Long Term Stability A = Accelerated Stability -20°C = Long term storage condition to support products that require freezing in all climatic zones as defined by ICH.

5°C = Long term storage condition to support products that require refrigeration in all climate zones as defined by ICH. Also, accelerated conditions for product that require freezing in all climate zones as defined by ICH.

250C/40%RH = Long term storage condition to support marketing of products in semi-permeable containers in Climatic Zones 1 and II as defined by ICH 300C/75%RH = Long term storage condition to support marketing in Climatic Zones III & IV.

The 30°C/75% RH condition is only required by a portion of the Zone IV markets, most notably Brazil and the ASEAN (Association of South East Asian Nations), but is also acceptable for markets that would accept lower humidity conditions. 40°C/25% RH = Accelerated storage condition for product in semi-permeable containers as defined by ICH 400C/75%RH = Accelerated storage condition to support Zones III&IV as defined by ICH.

25°C/60% RH may be used for product in semi-permeable containers if the appropriate development work has been done to determine the ratio of water loss between 40% and 60% relative humidity at 25°C.

Similarly, 40°C/75%RH may be used for the accelerated condition for product in semi-permeable containers, if the ratio of water loss between 25% and 75% relative humidity at 40°C has been determined. This can be achieved by experimentally determining the permeation coefficient for the container closure system or, as shown in the example below, using the calculated ratio of water loss rates between the two humidity conditions at the same temperature.

The permeation coefficient for a container closure system can be experimentally determined by using the worst case scenario (e.g., the most diluted of a series of concentrations) for the proposed drug product.

Examples can be found in the ICH Q1A(R2) reference. The need to include the Ph. Eur. Freedom from Microbiological Contamination Test in the protocol for stability studies on oral dosage products (e.g. at the beginning and end of long term study) should be considered and included in the protocol if necessary.

5.2.3.3 Bulk Package Stability 

A single batch of each MF or Art. No./bulk package combination shall be placed on stability to support transport and/or storage in the bulk container types intended to be used in commercial operations for transport and/or for storage periods of more than 30 days. The study conditions and length may vary according to how the bulk container is used in manufacturing operations.

Figure

Note 1

Initial results may be taken as the results of the batch release testing only when 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. See also Section 5.2.4.5 .

Normally, the study period for bulk packages shall be: 12 months, or 50% of the product expiry life if this is expected to be greater, at the long term storage condition and 3 months at a ‘more severe’ condition to cover potential short term excursions e.g. during transport; the conditions used being those selected for accelerated studies on the commercial primary packages.

These studies shall be conducted by Pharmaceutical and Analytical Research and Development (R&D) during the development phase of the product, on behalf of Operations. The stability profile in the bulk container should be no worse than that observed in the best primary package for that product. Otherwise, a limited time in the bulk package needs to be established and the shelf (expiry) life in the primary packages reduced accordingly.

The 30°C/75% RH condition is only required by a portion of the Zone IV markets, most notably Brazil and the ASEAN (Association of South East Asian Nations), but is also acceptable for markets that would accept lower humidity conditions.

5.2.4 General Requirements for Studies on New Commercial Products 

5.2.4.1 Temperatures shall be controlled to±20C 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 Normally, long term and accelerated stability studies shall be carried out on closed primary packages, without secondary packaging. Exceptions are: * When the secondary packaging affords additional protection for the product * When the secondary package affords no additional protection, but provides a convenient container for holding samples within the climate chamber, e.g. boxes of tablet blister strips.

5.2.4.3 Primary packages chosen for stability shall be taken in such a way, as they are representative of the entire batch. This does not preclude taking primary packages from a specific portion of the packaging run, if these are deemed to be representative of the entire batch.

5.2.4.4 All primary packages containing liquids shall be stored in an orientation that is the most stressful. This will be defined by R&D for each product. Provisions should be made for control samples for all primary packages to be stored in the upright position at the long term storage temperature/humidity condition. These control samples may serve as a reference in the event of a problem arising on stability.

5.2.4.5 To be acceptable for stability the time between manufacturing date and packaging date shall not exceed 6 months.

5.2.4.6 The time interval from commercial packaging to set down shall not exceed 60 calendar days. Additionally, should more than 30 calendar days elapse between initial release testing and set down, the non-microbial stability tests shall be repeated at the time of set down.

5.2.4.7 The set down date, i.e. time zero, shall be taken as the date the samples are placed in the climate chamber(s).

5.2.4.8 A separate primary package shall be withdrawn at each interval except for very large containers, where this is impractical, e.g. 5,000 cc bottle.

5.2.4.9 When samples are taken off test, they shall be stored within the labeled storage conditions for the product, and analysis completed within 30 calendar days unless test duration exceeds 30 calendar days.

5.2.5 Data Generation and Analysis 

5.2.5.1 All analytical and microbiological test methods shall be fully validated in accordance with ICH requirements (ICH Q 2) and the assays for drug and preservative content 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. If the test includes replicates, e.g. dissolution, do a minimum number as required by the method.

5.2.5.3 Documented procedures shall be used to investigate ‘out-of-specification’ results and report any confirmed ‘out-of-specification’ results to local senior QA management.

5.2.5.4 Record all results. This will normally be only one, but if more than one determination is carried out, compare each result with the specification. Act on any individual, confirmed ‘out-of-specification’ result.

5.2.5.5 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 to historical data, and where data is to be used to extend shelf (expiry) lives.

5.2.5.6 When required, transfer of test methods to a site shall be the subject of an analytical and/or microbiological technology transfer from PAR&D (new products) or from another commercial manufacturing site (established/mature products).

5.2.5.7 For sterile products, sterility tests on the initial and final sample pulls from each long term storage condition shall be performed. Where regulations permit, a container and closure integrity test may be used in lieu of sterility testing on samples other than the initial.

5.2.5.8 Policy on P.E.T. (Preservative Effectiveness Testing) For products marketed in the EU that contain a preservative and for which there is a quantitative specification and analytical method with sufficient precision and sensitivity to determine the concentration during commercial stability studies, compliance with the latest version of the European Pharmacopoeia, “Efficacy of anti-microbial preservation”, at the lower expiry life concentration of the preservative shall be demonstrated only during development of the product. For products marketed in the EU which contain a preservative for which there is no quantitative specification or analytical method with sufficient precision and sensitivity to determine the concentration during commercial stability studies, compliance with the latest version of the European Pharmacopoeia, “Efficacy of anti-microbial preservation”, shall be demonstrated at the initial and final time point of the long term storage condition. For products marketed in the USA that contain a preservative, the guidance issued by the FDA for post approval stability testing shall be followed.

5.2.5.9 Any reconstitution testing should be done in accordance with the protocol transferred from R&D.

5.2.5.10 Analytical results, which are numerical, shall have those results reported numerically instead of “complies” or “passes”, to allow for data evaluations and analysis.

5.3 Solid/Liquid Dosage Forms – Annual Maintenance Studies 

5.3.1 Selection of Batches/Primary Packages Each distinct commercial product/MF or Art. No./strength/primary package/packaging site combination from the Stability Site and its aligned Primary Packaging sites shall be included in the stability program, as detailed in the Stability Master Plan (SMP).

When a product/dosage strength is manufactured (formulated) at more than one site, additional studies will be conducted so that data are available to support every manufacturing (formulation) site/product/MF or Art. No./strength/primary package/packaging site combination. For solid dosage forms formulated at a site and supplied to more than one packaging site for primary packaging, a stability study will be set down to cover every manufacturing (formulation) site/product/MF or Art. No./strength/primary package/packaging site combination at least once every 5 years, either as an individual study, or by inclusion in a bracketed or matrixed study.

The use of bracketing or matrixing (e.g. strengths, primary packages) may be considered where technically justified and agreed with RA. Studies shall be conducted more frequently if required to meet specific regulatory requirements, e.g. on product/strength/primary package combinations marketed in USA and Canada.

5.3.2 Stability Protocols and Integrated Stability Protocols Integrated Stability Protocols, or individual market specific stability protocols, for studies on each product/primary package combination, shall be defined to meet the regulatory requirements of each country where it is marketed. Each study shall be referenced to the appropriate Integrated Stability Protocol or individual study protocol. The following sub-sections in Section 5.3 of this procedure summaries the general requirements of annual maintenance stability studies.

5.3.3 Study Conditions and Testing Schedules (Annual & Bulk Product Stability) The number of lots of drug product placed on stability and the frequency of testing shall be designed to confirm that commercial products continue to exhibit the same stability characteristics that were demonstrated in primary stability studies and the studies on the 3 first, or early, commercial scale batches.

5.3.3.1 Solid Dosage Forms The following table describes a reduced pull schedule for annual maintenance stability testing dependent on the expiry life of the product, ranging from 18 to 60 months. Application of this reduced pull schedule is dependent on the availability of data from previous studies conducted to the more detailed study conditions and testing schedules described in Section 5.2.3.1. For US studies, in addition to the dependence on available data from previous studies, additional time points may be necessary through agreement between the company and the regulatory reviewer.

Figure

Note 1

Initial results may be taken as the results of the batch release testing only when 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 and set down. See also Section 5.2.4.4 .

L = Long Term Stability -20°C = Long term storage condition to support products that require freezing in all climatic zones as defined by ICH.

5°C = Long term storage condition to support products that require refrigeration in all climate zones as defined by ICH.

25°C/60%RH = Long term storage condition to support marketing in Climatic Zones I and II defined by ICH.

Where product supplied in Zones I/II only, studies need to be stored and evaluated at the 25°C/60% RH condition. Where product supplied only in Zones III/IV only, studies need to be stored and evaluated at the 30°C/75% RH condition only. Where product supplied in both Zones I/II and Zones III/IV, then studies must be stored and evaluated at both conditions unless the 30°C/75%RH data supports the product’s registered shelf life in Zone I/II markets. However, if the removal of the 25°C/60% condition is considered, a RIAR (Regulatory Impact Assessment Report) shall be raised before implementation.

If product is stored in a hermetically sealed container, humidity control is not needed. 30°C/75%RH = Long term storage condition to support marketing in Climatic Zones III & IV. The 30°C/75% RH condition is only required by a portion of the Zone IV markets, most notably Brazil and the ASEAN (Association of South East Asian Nations), but is also acceptable for markets that would accept lower humidity conditions. The 60 month pull is required only for products with an already established 5 year shelf life .

.The shelf life of all products that currently have a shelf life of 4 years or less will not be extended beyond 4 years. These study conditions and testing schedules are geared to meet general ICH and tropical market licensing requirements.

The actual protocol conditions may differ depending on the product characteristics and these conditions will be established based upon the protocol developed to support the three first, or early, production scale batches.

If it is known from earlier studies that the product will not remain in specification when stored for 48 months at the long term storage conditions included in the table, the duration of long term studies can be reduced. If there is a cautionary labeling statement of ‘store below 25°C’ for a package marketed in Zones III/IV, the only long term storage condition required is 25C°/60% RH. Additionally, regulatory commitments may supersede the recommended protocol structure as presented above.

In any case, changes to registered elements of an existing protocol must be evaluated via the company’s change control processes. An additional time point corresponding to the expiration date may be required and should be considered on a case by case basis.

For products packaged in hermetically sealed containers that are stable for at least 3 years at 30°C and that are marketed in both Climatic Zones II and IV, the 25°C/60% RH condition can be omitted. The need to include the Ph. Eur..

Freedom from Microbiological Contamination Test in the protocol for stability studies on oral dosage forms products (e.g. at the beginning and end of long term study) should be considered and included in the protocol if necessary.

5.3.3.2 Liquids and Semi-solids 

For products such as solutions, suspensions etc., contained in primary packs designed to provide a permanent barrier to water loss, specific storage under conditions of high relative humidity is not necessary but the same range of temperatures and pull times shall be applied. Low relative humidity can adversely affect liquid and semi-solid products packaged in semi-permeable containers (e.g. solutions in plastic bags, nose drops in small plastic containers etc.) and consideration shall be given to appropriate testing under such conditions.

Figure

Note 1

Initial results may be taken as the results of the batch release testing only when 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 and set down.

See also Section 5.2.4.4 . L = Long Term Stability -20°C = Long term storage condition to support products that require freezing in all climatic zones as defined by ICH.

5°C = Long term storage condition to support products that require refrigeration in all climate zones as defined by ICH.

Also, accelerated conditions for product that require freezing in all climate zones as defined by ICH.

25°C/40%RH = Long term storage condition to support marketing in Climatic Zones I and II defined by ICH.

Where product supplied in Zones I/II only, studies need to be stored and evaluated at the 25°C/40% RH condition.

Where product supplied only in Zones III/IV only, studies need to be stored and evaluated at the 30°C/70% RH condition only. Where product supplied in both Zones I/II and Zones III/IV, then studies must be stored and evaluated at both conditions unless the 30°C/75%RH data supports the product’s registered shelf life in Zone I/II markets.

However, if the removal of the 25°C/60% condition is considered, a RIAR (Regulatory Impact Assessment Report) shall be raised before implementation. If product is stored in a hermetically sealed container, humidity control is not needed. 25°C/60% RH may be used if the appropriate development work has been done to determine the ration of water loss between 40% and 60% relative humidity at 25°C.

This can be achieved by experimentally determining the permeation coefficient for the container closure system or, as shown in the example below, using the calculated ratio of water loss rates between the two humidity conditions at the same temperature.

The permeation coefficient for a container closure system can be experimentally determined by using the worst-case scenario (e.g., the most diluted of a series of concentrations) for the proposed drug product. Examples can be found in the ICH Q1A(R2) reference. 30°C/75%RH = Long term storage condition to support marketing in Climatic Zones III & IV.

The 30°C/75% RH condition is only required by a portion of the Zone IV markets, most notably Brazil and the ASEAN (Association of South East Asian Nations), but is also acceptable for markets that would accept lower humidity conditions.

For products packaged in hermetically sealed containers that are stable for at least 3 years at 30°C and that are marketed in both Climatic Zones II and IV, the 25°/60° condition can be omitted. The need to include the Ph. Eur.

Freedom from Microbiological Contamination Test in the protocol for stability studies on oral dosage forms products (e.g. at the beginning and end of long term study) should be considered and included in the protocol if necessary.

5.3.3.3 Bulk Primary Package Stability 

Stability data on bulk package(s) intended to be used for new formulated product will have been generated during the development phase of a new product. However, there may be occasions when studies on formulated products in bulk packages may be required in Operations, e.g.

When a new or modified bulk container is introduced When no such data on established/mature products exist Typically, a ‘once only’ study, on each product /MF. or Article No./dosage strength/bulk package type combination shall be conducted to support transport and/or storage in the bulk container types intended to be used in commercial operations for storage over time periods of more than 30 days.

The study conditions and length may vary according to how the bulk container is used in manufacturing operations. In cases where the formulation range comprises the same excipients in slightly different proportions a bracketed study on the lowest and highest strength may be used to support the range. In cases where the formulation range comprises different compression weights of a common granulation, a study on one compression weight may be used to support all compression weights.

The study period on bulk packages used to store product for 12 months or more, and/or for transportation between manufacturing (formulation) sites and packaging sites, shall be 12 months or 50% of the product expiry life, which ever is longer and shall follow the schedule described in section 5.2.3.3.at the appropriate long term temperate storage condition, and 3 months at a ‘more severe’ condition to cover potential short term excursions e.g. during transport; the conditions used being those selected for accelerated studies on the commercial primary packs. If a significant body of information exist for the product, the number of time points may be reduced if the data supports such reduction. The stability profile in the bulk container should be no worse than that observed in the best finished package for that product. Otherwise, a maximum storage time in the bulk package needs to be established and the shelf (expiry) life in the primary packages reduced accordingly.

5.3.4 General Requirements for Annual Maintenance Studies 

The general requirements for studies on new products (see Section 5.2.4) shall apply to annual maintenance studies, except that the requirement to repeat the initial analysis if the set down occurs more than 30 days after the release testing is relaxed to 60 days providing that the first sample pull is 12 months or later.

5.3.5 Data Generation and Analysis 

The details given for studies on new products (see Section 5.2.5) shall apply to annual maintenance studies.

5.4 Product / Process Modification 

Where a drug substance/product, process, or primary package has been modified in a way that requires stability information to support the change, additional batches shall be entered in the commercial stability program. The test protocol, number of batches and primary packages variants shall be dependent upon the magnitude of the change and local regulatory requirements. During the MCM process, Regulatory, Operations QA, and possibly PAR&D, shall determine what stability studies are required to support the change. The DMG Stability Manager shall identify an appropriate existing Integrated Stability Protocol or create a new protocol if needed. Additionally, locally managed changes could require the initiation of stability studies. The following modifications are typical of situations, which may require additional stability studies. However, this is not an exhaustive list and use of the MCM process will determine the regulatory requirements.

 – Change in manufacturing process of the drug substance/drug product

 – Change in manufacturing site of the drug substance/drug product

 – Change in the formulation of the drug product

 – New strength addition of the drug product

 – Change in the batch size of the drug product

 – Reprocessing of the drug product