1 Purpose
The purpose of this document is to provide recommendations for performing and
documenting stability studies within R&D. Deviations from the recommended
practice may be made providing
* The scientific rationale can be justified against regulatory requirements and expectations. * There is no precedent that the scientific rationale will be unacceptable to regulatory authorities. * For formal stability studies, the deviations and scientific rationale justifying them, do not conflict with, or undermine the validity of stability studies on similar commercial product types, particularly those belonging to the same therapeutic area.In addition, this document describes the responsibilities of those involved with
stability studies. These responsibilities are the mandatory elements of this
guideline.
2 Scope and Applicability
This Guideline is applicable to all pharmaceutical drug Research and Development
R&D functions when either conducting or outsourcing any stability study during drug
development. For the drug development template refer to the Appendices.
Where stability data are provided in a regulatory submission, stability studies should
meet the appropriate regulatory requirements.
This guideline is applicable to the following:
* Drug substances * Drug products (including formulation intermediates and line extensions) * Comparators * Placebo productsThe general principals within this guideline should be considered for biotechnology
products however further guidance may be found in ICH guideline Q5C.
3 Definitions
3.1 Bracketing:
The design of a stability schedule such that only samples on the extremes of
certain design factors, e.g., strength, package size, are tested at all time points as
in a full design. The design assumes that the stability of any intermediate levels is
represented by the stability of the extremes tested. Where a range of strengths is
to be tested, bracketing is applicable if the strengths are identical or very closely
related in composition (e.g., for a tablet range made with different compression
weights of a similar basic granulation, or a capsule range made by filling different
plug fill weights of the same basic composition into different size capsule shells).
Bracketing can be applied to different container sizes or different fills in the same
container closure system.
3.2 Climatic zones:
The four zones in the world that are distinguished by their characteristic prevalent
annual climatic conditions.
Zone I : Temperate zone
Zone II : Mediterranean/subtropical zone
Zone III : Hot dry zone
Zone IV : Hot humid/tropical zone
3.3 Development stability studies:
Development stability studies provide stability data to support
* The use of drug substance and drug products in non-clinical studies(including safety studies) or clinical studies from Phase I to Phase III.
* Formulation and packaging development * Manufacturing and process development3.4 Formal stability studies:
Long term and accelerated (and intermediate) studies undertaken on primary
and/or commitment batches according to a prescribed stability protocol to
establish or confirm the re-test period of a proposed commercial drug substance
or the shelf life of a proposed commercial drug product.
3.5 ICH:
International Conference on Harmonisation
3.6 Investigational medicinal product (IMP):
A pharmaceutical form of an active substance or placebo being tested or used as a
reference in a clinical trial, including a product with a marketing authorization
when used or assembled (formulated or packaged) in a way different from the
authorized form, or when used for an unauthorized indication, or when used to
gain further information about the authorized form.
3.7 Investigational stability studies:
Studies on samples stored under extreme conditions e.g. elevated temperatures,
light, oxidation, pH and high humidity. Such stress tests are aimed to provide
preliminary information on substance degradation to help evaluate intrinsic
stability and degradation pathways and aid in the development of analytical
methodology.
Investigational studies also include initial compatibility studies to support formulation
development.
3.8 JNDA:
Japanese New Drug Application.
3.9 MAA:
Marketing Authorization Application including JNDA and NDA.
3.10 Matrixing:
The design of a stability schedule such that a selected subset of the total number
of possible samples for all factor combinations is tested at a specified time point.
At a subsequent time point, another subset of samples for all factor combinations
is tested. The design assumes that the stability of each subset of samples tested
represents the stability of all samples at a given time point. The differences in
samples for the same drug product should be identified as, for example, covering
different batches, different strengths, different sizes of the same container closure
system and possibly in some cases, different container closure systems.
3.11 NDA:
New Drug Application
3.12 Re-test date:
The date after which samples of the drug substance should be examined to ensure
the material is still in compliance with the specification and suitable for use in the
manufacture of a given drug product. Excipients normally have re-test dates.
3.13 Re-test period:
The period of time during which the drug substance is expected to remain within
its specification and, therefore can be used in the manufacture of a given drug
product, provided that the drug substance has been stored under the defined
conditions. After this period, a batch of drug substance destined for use in the
manufacture of a commercial drug product should be re-tested for compliance
with the specification and then used immediately. A batch of drug substance can
be re-tested multiple times and a different portion of the batch used after each re-
test, as long as it continues to comply with the specification.
Drug substances destined for use in the manufacture of investigational medicinal
products once re-tested for compliance with the specification at the end of the re-
test period, may have the re-test period extended as appropriate, based on the long
term accumulated data.
3.14 Shelf life:
The time period during which a drug product is expected to remain within the
approved specification, provided that it is stored under the conditions defined on
the container label.
4 Responsibilities
It is the responsibility of R&D to generate stability data to a scientific level that
supports the development, production and worldwide marketing of a drug product.
4.1 R&D Line Management
R&D Line Management, as defined in local procedures, supported by or in conjunction with other relevant personnel where appropriate, is responsible for: The principles of a stability program for drug substances, drug products, comparators and placebo products at all stages of drug development An awareness of approved and draft stability guidelines Assessing if reduced stability programs can be applied Appropriate consultation with Regulatory CMC and subsequently if necessary with relevant authorities Ensuring that suitable batches are placed on stability Documenting and approving stability protocols according to local procedures Evaluating stability data against acceptance criteria and reporting data according to GEL templates and local procedures Assigning appropriate re-test periods, shelf lives and storage conditions for drug substances, investigational medicinal products, excipients and comparators and updating when more data become available Assigning re-test periods, shelf lives and storage conditions to be included in the MAA Ensuring the hand over of stability studies to Operations and agreeing together the stability protocols for commitment and annual maintenance batches in the MAA 4.2 R&D QA QA is responsible for: Releasing batches of drug substances and drug products for formal (MAA) stability studies. It is not necessary for QA to release batches of drug substances and drug products prior to the start of a stability study, providing there is no undue delay. A risk assessment for the project is recommended under these circumstances.5 Guideline
This section of the Stability Guideline provides recommendations on
stability testing requirements, however provides the flexibility to use alternative
approaches where there are scientifically justifiable reasons.
Stability testing will provide evidence on the quality of the material tested under
the influence of a variety of environmental factors such as temperature, humidity,
and light and how the materials quality varies with time. Stability data are used
to establish a re-test period for a drug substance or shelf life for a drug product
and the recommended storage conditions.
Stability studies within R&D can be classified as
* Investigational stability studies (preliminary stress/compatibility) * Development stability studies (to support non-clinical/clinical studies andadditional stress/compatibility)
* Formal stability studies on primary batches (for MAA)Protocols should be prepared at all stages so that it is clear what should be done.
The level of details will increase during development. Example protocols are
presented for guidance in the Appendices, see 9.1. Supplementary guidance on
recommended test conditions for drug substances and drug products is provided
in the Appendices see 9.3.
5.1 Investigational stability studies
Within R&D, when a new drug substance enters development a quick assessment of
the stability characteristics is required. Compatibility studies to support formulation
development may also be required and drug products should be evaluated at
appropriate conditions to understand degradation pathways.
Significant levels of physical or chemical degradation can help to understand
degradation pathways and develop stability indicating methods. As a minimum,
one batch of drug substance and drug product should be tested.
Investigational studies should involve conditions that evaluate thermolytic,
hydrolytic, oxidative and photolytic degradation pathways.
Stability data generated for investigational studies are not normally included in
any type of clinical application.
5.2 Development stability studies
The amount of stability data collected to support non-clinical and clinical studies
will depend on the length of the studies and the complexity of the investigational
material. Normally one batch is tested.
In development studies, drug substance and product stability protocols should be
derived from available forced degradation stability data such that appropriate
long term, accelerated and stressed conditions are selected. Samples should be
examined for those features susceptible to change during storage and likely to
influence quality, safety and/or efficacy. For drug products, bracketing may be
applied when a range of strengths, and different drug/excipient ratios are being
developed. One batch of each formulation, strength or pack type is typically
tested. A matrixing design may also be appropriate.
Using development stability data, re-test periods for drug substances and shelf
lives for drug products should be established for non-clinical and clinical
material. Extrapolations may be used, see 5.14.
Stability studies in bulk packs used for intermediate storage of investigational
medicinal products should be considered especially in Phase III. Prior to Phase
III, a shelf life may be assigned to bulk material using appropriate open dish
stability data.
For drug substances, development stability studies should also:
Identify any change in physical characteristics and the solid state degradationproducts that are likely to occur under long term and accelerated storage
conditions that will be encountered when stored as directed
For drug products, development stability studies should also:
Identify formulation degradation products produced when stored in theprimary pack under controlled conditions which model the real time storage
conditions which are likely to be encountered when the product is stored as
intended by a target commercial label
Identify any interactions with excipients, packaging and container orientationto support formulation and/or packaging development.
Monitor changes in product performance characteristics Test in-use stability and sensitivity to other types of stress refer to 5.10 and5.11.
In addition, for both drug substances and products, stability studies should:
Identify influences from production/processing parameters Identify any specific packaging or labeling requirementsIt is recognized that changes may occur to raw material or intermediate sources,
synthetic route and formulation composition and equipment and scale during
development. Each change should be considered in the context of whether further
stability testing of materials produced by the new process is required. If there is a
significant change in formulation then additional stressed/forced degradation testing
may be required.
If appropriate, results of development stability studies may be included in the MAA
as supporting stability data.
For Phase IV (post approval) studies, material may be provided in a pack other
than the commercial one. This should be covered by stability data.
Example stability protocols for investigational medicinal products are found
within the Appendices, see 9.1. The time points suggested are typical.
5.3 Formal stability studies
Formal stability studies should be conducted for the MAA on drug substances
and drug products representative of the final commercial process and pack and
show that the drug substance or product remains within the proposed specification
during the proposed period, stored as recommended.
Formal stability studies should be conducted as detailed in the current ICH guideline
Q1A, where guidance on batch selection, manufacturing process, scale of
manufacture, input materials and protocol design is provided. Photostability
studies should be conducted according to the current ICH guideline Q1B. For the
evaluation of stability data, consult the current ICH guideline Q1E. When
bracketing and matrixing are applied to formal stability studies, the current ICH
guideline of Q1D should be referred to.
The re-test date for drug substances and shelf life for drug products will be assigned
following evaluation of the data according to current ICH guideline Q1E, considering
an appropriate specification and comparison with the current ICH guidelines Q3A or Q3B.
It is recommended that formal stability studies be conducted up to five years for
drug substances and three years for drug products. Bulk packs (one batch for bulk
products) should be studied for 12 months or more if not covered by stability data
from other studies. Accelerated data should be considered if the bulk pack would
be used for transportation.
For a new chemical entity (NCE), normally 12 months data are presented in the
MAA at time of submission for both the drug substance and drug product. A
reduced stability data package (e.g. 6 months) may be permissible at the time of
submission. The regulatory agency should be contacted before a reduced stability
program not following ICH guidelines is planned for the MAA.
If there is a major change in formulation between Phase III and the final formulation
then additional testing may be required. These data are typically submitted in the
MAA.
If formal stability batches are not manufactured at the commercial site then
regulatory advice should be sought when entering the development for launch
phase to discuss the need for site specific stability data for the US. At least 3
months stability data on at least one batch manufactured at the commercial site
may be required (particularly for complex drug products) for the US, in the
MAA.
When conducting formal stability studies for drug products there are different
approaches to take based on the data generated from development stability
studies. Refer to 9.1 Appendices, for the recommended protocols on
* Stable drug products * Less stable drug products5.4 Drug product line extensions
Treat drug product line extensions as new drug products and conduct stability
studies according to guidance detailed in 5.2 and 5.3. A reduced stability data
package may be acceptable for the regulatory submission. If the drug substance
manufacturing process is unchanged further stability studies are not necessary.
5.5 Comparators
Comparators used in a clinical trial should be stability tested if modified (e.g.
encapsulated, reformulated or re-packed in packs less protective than the original
pack). As a minimum, one batch is recommended at the long term condition and
optional testing at the accelerated condition to support extrapolation of shelf life.
Consider also placing the unmodified comparator on stability as a reference.
Evaluate testing, at least for appearance. For a comparator product in its original,
or equivalent, package no stability testing is needed.
Stability information on comparators may be found in the literature to support
shelf life decisions. If a modification results in a formulation or pharmaceutical
form that differs significantly from the commercial product, consider collecting
some accelerated stability data in a pre-study.
5.6 Placebo
In some cases, consider testing at least for appearance.
5.7 Holding times and storage of drug product intermediates
Consider providing stability data if the holding times and storage of drug product
intermediates (e.g. bulk solutions or granules) exceeds 30 days. Currently, there
are no guidelines stating maximum allowed holding times of intermediates,
however such stability data are used by Operations post registration to support
products with several discontinuous manufacturing steps.
When the final process is settled it is recommended to manufacture one batch
using the planned maximum holding time for each intermediate. This batch,
representing the longest possible process time should be stability tested at long
term and accelerated conditions.
A shelf life calculated from the last step in the manufacturing process could be
justified when a cumulative hold time stability study of the drug product has been
performed demonstrating appropriate stability (Regulatory approval is needed).
Therefore with suitable cumulative hold time stability data, the date of
manufacture is not the date that the first processing step is performed combining
the drug substance with other ingredients. Where necessary, consider providing
cumulative stability data for the drug product in the first MAA.
5.8 Bracketing and matrixing
Refer to ICH guideline Q1D. It is acceptable to use bracketing and matrixing for
formulations that are not so closely related with justification provided from
supporting data. When applying bracketing and matrixing to different pack types
and sizes etc, the bulk sample is normally tested instead of each variant at the
initial time point.
5.9 Packaging
Global guidance and the local interpretation of this guideline should be
considered when selecting the packaging for development studies. For formal
stability studies drug substances should be packaged in a container closure system
that is the same or simulates the packaging proposed for storage and distribution.
For drug product the primary pack should be that of the proposed commercial
drug product. Any secondary pack should be evaluated if it affords additional
protection, other than physical, of the product. If it is found that the secondary
package improves the stability of the product, the primary batches studied should
be packed and stored with a representative secondary package in place. In some
cases, stability data should be generated in the absence of a protective secondary
pack to justify a suitable in use shelf life. Where a packaging device provides a
specific functionality, consider the need to test the packaging performance alone
in a separate stability study.
5.10 Transportation studies
To recommend special transportation and storage conditions for investigational
medicinal products and justify temperature excursions consider if temperature
cycling is also appropriate in development studies. Temperature cycling is
normally conducted during formal stability studies. For certain drug products it is
a regulatory requirement to submit temperature cycling studies in the MAA, eg
for suspensions and creams this is a US regulatory requirement. Cycling
conditions will depend on the conditions that the product may be exposed to once
the product is in distribution and use. If temperature cycling is performed in early
development and there is any change in formulation or analytical methodology
consider repeating cycling studies in parallel to formal studies.
A temperature cycling study for drug products that may be exposed totemperature variations above freezing may consist of three cycles of two
days at refrigerated temperature (2-8°C) followed by a minimum of two
days at 40°C.
- A temperature cycling study for drug products that may be exposed to sub-
freezing temperatures may consist of three cycles of two days at freezer
temperature (- 20°C± 5°C) followed by a minimum of two days at 40°C.
Consider testing at the long term condition following temperature cycling.
For inhalation aerosols, the recommended cycle study (specified by the US)consists of three or four six-hour cycles per day, between sub-freezing
temperature and 40°C for a period of up to six weeks. Seek regulatory
advice for other territories.
For frozen drug products, the recommended cycle study should include anevaluation of effects due to accelerated thawing in a microwave or a hot
water bath unless contraindicated in the labeling.
5.11 In-use stability
The purpose of in-use stability testing is to establish the period of time during
which a product can be used whilst retaining acceptable quality once the
container is opened and the first dose is removed. Specific parameters, eg
preservatives, need to be studied. For more detailed information, see CPMP,
Where relevant, studies on diluted or reconstituted material must be performed.
To accommodate certain specific pharmacy dosing regimes, up to 3 months open
storage may be required.
5.12 Samples for stability testing
Sampling should produce a representative sample of the batch for stability
testing. This can be accomplished by taking a random sample of containers or
units from the finished batch. A stratification plan may be used whereby at a
random starting point every nth unit is taken from a filling or packaging line
(where n is chosen such that the sample is spread over the whole batch), or by
some other plan designed to ensure an unbiased selection.
Sampling for formal stability studies should be documented.
5.13 Timings
Stability studies should preferably be set down within 3 months from the date of
manufacture. If release testing is performed, these data can also serve as the
initial time point if the start of storage is within 1 month from the release date (for
stable material longer times may be justified).
A general rule is that samples should be pulled from climatic chambers on the
planned pull date, or latest within 2 weeks after the planned pull date when
storage time is≤12 months and within 4 weeks after the planned pull date when
storage time is >12 months. All samples should be tested within 1 month of the
pull date, however for more complex drug products longer analysis times may be
justified.
5.14 Shelf life and re-test period
For a drug substance the re-test date is calculated from the date of manufacture,
i.e. the date of completion of the final purification step of the final drug
substance. For a drug product the shelf life is normally calculated from the date
of manufacture, the date, which the first step, is performed combining the drug
substance with other ingredients. Refer to 5.7 for exceptions.
5.14.1 Re-test/shelf life predictions for material used in non-clinical and clinical studies
During the development of a new drug substance and drug product, when only
limited long term stability data are available, it is acceptable to evaluate stressed
and accelerated stability data and if satisfactory, extrapolate a re-test period/shelf
life for material used in non-clinical and clinical studies, which is longer than the
amount of real time stability data accumulated. Guidance on extrapolation of data
is provided in the Appendices, see 9.2.
Stability data available for similar drug product formulations or from investigational
work may be used as supporting evidence for the assignment of an extrapolated shelf life.
The maximum extrapolated re-test period or shelf life should be based on there being
‘no significant change’ (ie the change is measurable but remains within the
definition in ICH guideline Q1A) at the stated condition. It is acceptable to
evaluate available stability data and extend the re-test period or shelf life longer
than the accumulated real time stability data. This extended re-test period or
shelf life should be confirmed with real time data.
For practical reasons a shelf life of at least 24 months is normally required for
Phase III investigational medicinal products. For less stable or complex formulations
more conservative extrapolations of stability data may apply.
Microbiological considerations should be taken into account when assigning a
shelf life. The manufacturing procedure and the presence / absence of a
preservative should be considered prior to assigning a shelf life and storage
condition.
5.14.2 Re-test/shelf life predictions for commercial material
In addition to the commercial shelf lives proposed according to current ICH
guideline Q1E, consideration should be given to any specific territorial
requirements. Guidance on this and other territory specific requirements should
be available from Regulatory CMC.
5.14.3 Re-test date for excipients
For commercially available excipients, published stability data should be
available from the vendor and the recommended re-test date should be observed.
5.14.4 Shelf life for comparators
An unmodified product in the original primary pack or repackaged into a
packaging giving equivalent protection should be given the shelf life assigned to
the original product. Where stability data are generated on a modified product,
extrapolations may be made and any shelf life assigned should not be beyond that
of the shelf life of the unmodified commercial product.
5.14.5 Shelf life for placebo
Placebos formulations from standard excipients should be assigned a default shelf
life according to local procedures. Where placebos have been stability tested at least
for description, extrapolations may be made confirmed by real time data.
5.15 Storage conditions
Information on appropriate storage conditions should be given on labels for
investigational material and for marketing according to available regulatory
guidelines.
Appendix