STABILITY STUDY OF

DRUG PRODUCT
Cervantes, Cruz, Esteves, Mas, Samonte
What is stability?
■ an essential factor of quality, safety and efficacy of a drug product.
Insufficient stability of a drug product can result in changes in physical
(like hardness, dissolution rate, phase separation, etc.) as well as in
chemical characteristics (formation of high risk decomposition
substances)

■ determine the shelf-life, namely the time period of storage at a

specified condition within which the drug product still meets its
established specifications.
Stability Testing

■ determine the shelf-life, namely the time period of storage at a

specified condition within which the drug product still meets its
established specifications
■ consists of a series of tests in order to obtain an assurance of stability
of a drug product, namely maintenance of the specifications of the
drug product packed in its specified packaging material and stored at
the established storage condition within the determined time period
■ should be biased towards more stressful rather than less stressful
conditions
Objectives of Stability Testing
■ It is intended to provide recommendations on the core stability study
package required for drug products, but leaves sufficient flexibility to
encompass the variety of different practical situations that may be
encountered due to specific scientific considerations and
characteristics of the products being evaluated. (ASEAN, 2013).
Other Reasons for Performing Stability
Testing
■ to provide evidence on how the quality of a drug substance or drug
product varies with time under the influence of a variety of
environmental factors, such as temperature, humidity, and light (ICH
Q1A, 2003)

■ to establish a retest period for the drug substance or a shelf life for
the drug product and recommended storage conditions (ICH Q1A,
2003)
Scope of Stability Testing

■ This guideline addresses the information to be submitted during

application for marketing authorization/registration and variations of
drug products in ASEAN Member States.

■ The drug products covered in this guideline include NCE, Generics and
Variations (MaV and MiV) but exclude biologicals and drug products
containing vitamin and mineral preparations.
 Design of Stability Testing

General Storage Conditions

Photostability Testing In-use Stability
Selection of Batches Container Closure System
Specification Evaluation
Testing Parameters Stability Commitment
Testing Frequency Statements/Labeling
 WHO:
STABILITY
TESTING
PRINCIPLES
Objectives
■ to exemplify the core stability data package required for
registration of active pharmaceutical ingredients (APIs) and
finished pharmaceutical products (FPPs)
■ these guidelines should also be applied to products that are
already being marketed, with allowance for an appropriate
transition period, e.g. upon re-registration or upon re-
evaluation
Scope
■ New and existing APIs
■ Address information to be submitted in original and
subsequent applications for marketing authorization of their
related FPP for human use
■ Not applicable to stability testing for biologicals
General Prinicples
■ Provide evidence of how the quality of an API or FPP varies with time under the
influence of:
– Temperature
– Humidity
– Light
■ Study of product-related factors that influence its quality
– interaction of API with excipients
– container closure systems
– packaging materials
– interaction between two or more APIs (in FDC FPP)
2.1 Active Pharmaceutical Ingredient (API)
2.1.1 General 2.1.7 Storage conditions
2.1.2 Stress testing 2.1.8 Stability
2.1.3 Selection of batches commitment
2.1.4 Container closure 2.1.9 Evaluation
system 2.1.10 Statements and
2.1.5 Specification labelling
2.1.6 Testing frequency 2.1.11 Ongoing stability
studies
2.1.1 General
 Testing parameters:
- Appearance
- Assay
- Degradation products
- Other parameters susceptible to change

 The re-test period or shelf-life assigned to the API by the API

manufacturer should be derived from stability testing data.
2.1.2 Stress testing

 When available, it is acceptable to provide the

relevant data published in the scientific literature
to support the identified degradation products
and pathways
 When no data are available, stress testing
should be performed
2.1.2 Stress testing

■ The nature of the stress testing will depend on the individual API and the type of FPP
involved
■ Should include effect of:
– Temperature (in 10 °C increments above the temperature used for accelerated
testing)
– Humidity (75% RH or greater)
– Oxidation and photolysis
■ The testing should also evaluate the susceptibility of the API to hydrolysis across a
justified range of pH values when in solution or suspension.
2.1.3 Selection of batches

■ Data from at least three primary batches of the API should normally be provided
■ Batches should be
– manufactured to a minimum of pilot scale by the same synthesis route as
production batches
– using a method of manufacture and procedure that simulates the final process
to be used for production batches
– overall quality placed on stability studies should be representative of the
quality of the material to be made on a production scale
■ For existing active substances that are known to be stable, data from at least two
primary batches should be provided.
2.1.4 Container closure system

■ The stability studies should be conducted on the API packaged in a container

closure system that is the same as, or simulates, the packaging proposed for
storage and distribution.
2.1.5 Specification

■ Test attributes that are susceptible to change during storage and are likely to
influence quality, safety and/or efficacy
– Physical
– Chemical
– Biological
– Microbiological
■ Whether and to what extent replication should be performed will depend on the
results from validation studies.
2.1.6 Testing frequency

Storage condition Shelf-life Testing frequency

0, 3, 6, 9, 12, 18, 24,
Long term 12 months
48, 72 months
6 months 0, 3, 6 months
Accelerated
12 months 0, 6, 9, 12 months
2.1.7 Storage conditions

■ General case
2.1.7 Storage conditions

■ API intended for storage in a refrigerator

■ API intended for storage in a freezer

2.1.7 Storage conditions

■ API intended for storage below -20°C

– Should be treated on a case-by-case basis
2.1.8 Stability commitment

■ When the available long-term stability data on primary batches do not cover the
proposed re-test period granted at the time of approval, a commitment should be
made to continue the stability studies post-approval in order to firmly establish the
re-test period or shelf-life.
2.1.9 Evaluation

■ Purpose: to establish a re-test period applicable to all future batches manufactured

under similar circumstances
■ To analyze data that is expected to change over time, determine the time at which
the 95% one-sided confidence limit for the mean curve intersects the acceptance
criterion
– If batch-to-batch variability is small, combine data into one overall estimate
(through statistical tests)
– If unable to combine data, overall re-test period should be based on the
minimum time a batch can be expected to remain within acceptance criteria
2.1.10 Statements and labelling

■ Storage statement should be established for display on the label.

■ Where applicable specific instructions should be provided, particularly for APIs that
cannot tolerate freezing or excursions in temperature.
■ Avoid “ambient conditions” or “room temperature”.
■ A retest date should be displayed on the container label if appropriate.
2.1.11 Ongoing stability studies

■ Purpose: to monitor the API and to determine that the API remains, and can be
expected to remain, within specifications under the storage conditions indicated on
the label, within the re-test period in all future batches

■ Ongoing stability programme should be described in a written protocol and the

results presented in a formal report
2.1.11 Ongoing stability studies

■ Parameters:
– number of batch(es) and different batch sizes, if applicable;
– relevant physical, chemical, microbiological and biological test methods;
– acceptance criteria;
– reference to test methods;
– description of the container closure system(s);
– testing frequency;
– description of the conditions of storage (standardized conditions for long-term
testing as described in these guidelines, and consistent with the API labelling,
should be used); and
– other applicable parameters specific to the API
2.2 Finished Pharmaceutical Product
(FPP)
2.2.1 General 2.2.8 Evaluation
2.2.2 Selection of batches 2.2.9 Statements and labelling
2.2.3 Container closure system 2.2.10 In-use stability

2.2.4 Specification 2.2.11 Variations

2.2.12 Ongoing stability studies
2.2.5 Testing frequency
2.2.6 Storage conditions
2.2.7 Stability commitment
2.2.1 General

■ Design of the stability studies should be based on

– knowledge of the behavior and properties of the API
– information from stability studies on the API
– experience gained from pre-formulation studies and investigational FPPs
2.2.2 Selection of batches

■ Data from stability studies should be provided on at least three primary batches of
the FPP.
■ Primary batches:
– same formulation and packaged in the same container closure system
– manufacturing process should simulate that to be applied to production
batches, should provide product of the same quality and meeting the same
specification as that intended for marketing
■ Stability studies should be performed on each individual strength, dosage form and
container type and size of the FPP
2.2.3 Container closure system

■ Conducted on the dosage form packaged in the container closure system proposed
for marketing
■ Available studies carried out on the FPP outside its immediate container or in other
packaging materials can form a useful part of the stress testing of the dosage form
or can be considered as supporting information, respectively
2.2.4 Specification

■ Test attributes that are susceptible to change during storage and are likely to
influence quality, safety and/or efficacy
– Physical
– Chemical
– Biological
– Microbiological
– Preservative content
– Functionality tests
■ Testing Parameters (specific to dosage form)
2.2.4 Specification

■ Shelf-life acceptance criteria should be derived from consideration of all available

stability information
■ Any differences between the release and shelf-life acceptance criteria for
antimicrobial preservative content should be supported by a validated correlation of
chemical content and preservative effectiveness
■ A single primary stability batch of the FPP should be tested for effectiveness of the
antimicrobial preservative at the proposed shelf-life for verification purposes
2.2.5 Testing frequency
Storage condition Shelf-life Testing frequency
0, 3, 6, 9, 12, 18, 24,
Long term 12 months
48, 72 months
Accelerated 6 months 0, 3, 6 months
Intermediate 12 months 0, 6, 9, 12 months
2.2.6 Storage conditions

■ Should be evaluated under storage conditions that will test the FPP’s
– Thermal stability
– Sensitivity to moisture
– Potential for solvent loss
■ Photostability testing, orientation
2.2.6 Storage conditions

■ Storage condition tolerances - the acceptable variations in temperature and relative

humidity of storage facilities
■ The storage conditions and the lengths of studies chosen should be sufficient to
cover storage, shipment and subsequent use with due regard to the climatic
conditions in which the product is intended to be marketed
2.2.6 Storage conditions

■ General case
2.2.6 Storage conditions

■ FPPs packaged in impermeable containers

– Parameters will depend on characteristics of packaging material
– Suitability of packaging material used is determined by product characteristics

– Stability studies can be conducted under any controlled or ambient relative

humidity condition
2.2.6 Storage conditions

■ FPPs packaged in semi-permeable containers

2.2.6 Storage conditions

■ FPPs intended for storage in a refrigerator

■ FPPs intended for storage in a freezer

2.2.6 Storage conditions

■ FPPs intended for storage below -20⁰C

– Should be treated on a case-by-case basis
2.2.7 Stability commitment

■ When the available long-term stability data on primary batches do not cover the
proposed re-test period granted at the time of approval, a commitment should be
made to continue the stability studies post-approval in order to firmly establish the
re-test period or shelf-life.
2.2.8 Evaluation

Systematic approach should be done, and should include results from

– Physical, chemical, biological, microbiological tests
– Particular attributes of dosage form
■ Purpose: to establish a shelf-life and label storage instructions applicable to all
future batches manufactured under similar circumstances
2.2.8 Evaluation

■ Provisional shelf-life of 24 months may be established provided:

– The API is known to be stable (not easily degradable)
– Stability studies have been performed and no significant changes have been
observed
– Supporting data indicate that similar formulations have been assigned a shelf-
life of 24 months or more
– The manufacturer will continue to conduct long-term studies until the proposed
shelf-life has been covered, and the results obtained will be submitted to the
national medicines regulatory authority
2.2.9 Statements and labelling

■ Storage statement should be established for the label based on the stability
evaluation of the FPP.
■ Where applicable specific instructions should be provided, particularly for FPPs that
cannot tolerate freezing.
■ Avoid “ambient conditions” or “room temperature”.
■ An expiry date should be displayed on the container label.
■ FPPs should be packed in containers that ensure stability and protect the FPP from
deterioration.
2.2.10 In-use stability

■ Purpose: to provide information for the labelling on the preparation, storage

conditions and utilization period of multi-dose products after opening, reconstitution
or dilution of a solution
■ The test should be designed to simulate the use of the FPP in practice
■ The physical, chemical and microbial properties of the FPP susceptible to change
during storage should be determined over the period of the proposed in-use shelf-
life
2.2.11 Variations

■ Additional stability studies are required whenever variations that may affect the
stability of the API or FPP are made
■ Variations may include:
– change in the manufacturing process
– change in the composition of the FPP
– change of the immediate packaging
– change in the manufacturing process of an API
2.2.12 Ongoing stability studies

■ Purpose: to monitor the product over its shelf-life and to determine that the product
remains, and can be expected to remain, within specifications under the storage
conditions on the label

■ Ongoing stability programme should be described in a written protocol and results

formalized as a report
2.2.12 Ongoing stability studies

■ Purpose: to monitor the product over its shelf-life and to determine that the product
remains, and can be expected to remain, within specifications under the storage
conditions on the label

■ Ongoing stability programme should be described in a written protocol and results

formalized as a report
2.1.11 Ongoing stability studies

■ Parameters:
– number of batch(es) per strength and different batch sizes, if applicable. The batch
size should be recorded, if different batch sizes are employed;
– relevant physical, chemical, microbiological and biological test methods;
– acceptance criteria;
– reference to test methods;
– description of the container closure system(s);
– testing frequency;
– description of the conditions of storage (standardized conditions for long-term
testing as described in these guidelines, and consistent with the product labelling,
should be used); and
– other applicable parameters specific to the FPP
STABILITY
TESTING
PRINCIPLES
Based on International Conference
on Harmonisation on Technical
Requirements for Registration of
Pharmaceuticals for Human Use
Sections:
Q1A(R2) Stability Testing of New Drug Substances and Products

Q1B Stability Testing: Photostability Testing of New Drug Substances and Products

Q1C Stability Testing for New Dosage Forms

Q1D Bracketing and Matrixing Designs for Stability Testing of New Drug Substances
and Products

Q1E Evaluation of Stability Data

Q1F Stability Data Package for Registration Applications in Climatic Zones III and IV
DEFINITION
OF TERMS
ICH STABILITY TESTING GUIDELINES
 Accelerated vs Long-Term Testing

■ Accelerated Testing
-studies which increase the rate of chemical
degradation or physical change thru exaggerated storage
conditions

■ Long Term (Real-Time) Testing

- Studies conducted during and beyond the expected
shelf-life and storage periods of samples under the storage
conditions expected in the intended market
 Matrixing vs Bracketing

■ Matrixing
-Designs in which a selected subset of samples is
tested, e.g. different strengths, container/closure systems,
batches

■ Bracketing
-design of a stability schedule such that only samples
on the extremes of certain design factors (e.g., strength,
container size and/or fill) are tested at all time points as in a
 Retest vs Shelf Life Period

■ Retest Period
-within specification when stored under the recommended
conditions in the proposed bulk storage

■ Shelf Life Period

-within the approved shelf life specification, provided that it
is stored under the conditions defined on the container label.
 Release vs Shelf Life Specs

■ Specification – Release
- determine the suitability of a drug product at the time
of its release.

■ Specification - Shelf life

- determine the suitability of a drug substance
throughout its re-test period, or that a drug product should
meet throughout its shelf life.
STABILITY
TESTING
PRINCIPLES
FOR DRUG PRODUCTS
1.) Selection of Batches Data
-should be provided on at least three
primary batches of the drug substance

2.) Container Closure System

- same as or simulates the packaging
proposed for storage and distribution
FOR DRUG PRODUCTS
3.) Testing Frequency

a.Long term studies -> sufficient to establish

the stability profile of the drug substance

b. Drug substances with a proposed re-test

period of at least 12 months -> every 3
months over the first year, every 6 months
over the second year, and annually
thereafter through the proposed re-test
period.
FOR DRUG PRODUCTS

4.) Storage Testing

-long term testing -> minimum of 12 months’
duration on at least three primary batches at
the time of submission and should be
continued for a period of time sufficient to
cover the proposed re-test period.

-Climatic zone of Philippines: IV (Hot and

Humid)
STORAGE CONDITIONS

4.1) General Case

4.2) Refrigerator
Storage
STORAGE CONDITIONS

4.3) Freezer

4.4) Below Freezer Point: Case to case basis

FOR DRUG PRODUCTS

5.) Stability Commitment

- when available long term stability data on
primary batches do not cover the proposed re-test period
granted at the time of approval, a commitment should be
made to continue the stability studies post approval in order
to firmly establish the re-test period.

6.) Photostability Testing

- conducted on at least one primary batch of the drug
FOR DRUG PRODUCTS

6.) Photostability Testing

1.) forced degradation testing
2.) confirmatory testing

Purpose: evaluate the overall photosensitivity

of the material for method development
purposes and/or degradation pathway
elucidation

Method: Quinine Chemical Actinometry

FOR DRUG PRODUCTS

7.) Evaluation
-statistical analysis between batches
Reason:
- degree of variability of individual batches affects the
confidence that a future production batch will remain
within specification throughout the assigned re-test
period

-should include not only the assay, but also the levels
of degradation products and other appropriate attributes
FOR DRUG PRODUCTS

8.) Statements/Labeling
-in accordance with relevant national/regional
requirements
-should be based on the stability evaluation of
the drug substance
-Avoid using “ambient conditions” or “room
temperature”
 PHARMACEUTICAL
INSPECTION CONVENTION

PHARMACEUTICAL
INSPECTION CO-OPERATION
SCHEME

Guide to Good Manufacturing Practice

for Medicinal Products
General
■ facilitate removal of barriers to trade in
medicinal products

■ promote uniformity in licensing

decisions

■ ensure maintaining of high standards

of quality assurance in development,
manufacture and control of medicinal
products
History (PIC/S GMP Guide Part I)
PIC Basic Standards of 1972
– derives from WHO GMP Guide; was further developed:
(1) to comply with stringent manufacturing and health requirements in PIC/S
countries and
(2) to adapt to scientific and industrial technology –

AIM: to ensure that high quality medicines were produced in line with the PIC
Convention and then the PIC Scheme
History (PIC/S GMP Guide Part I)
Some differences between the two Guides:
■ the definition of Pharmaceutical Product (referred to as “Medicinal
Product” in this Guide), which is found in Article 1 of the Pharmaceutical
Inspection Convention, has been retained;
■ references to the EU Directives, as well as to MRAs, have been deleted;
■ the expression “authorised person” (see Glossary) is used in the PIC/S
Guide while the expression “Qualified Person” is used in the EU Guide;
■ since not all Participating Authorities under the PIC Scheme are parties to
the European Pharmacopoeia Convention, the mention of “European
Pharmacopoeia” in the Guide has been amended to read “European or
other relevant Pharmacopoeia”
History (PIC/S GMP Guide Part I)
Good Manufacturing Practice Guide for Active Pharmaceutical
Ingredients (ICH Q7A) – adopted by the PIC/S Committee on
May 22, 2001 as stand-alone guide (PE 007)

- first draft of GMP Guide for APIs was elaborated by PIC/S before it
was transferred to ICH
- PIC/S Committee decided to make it Part II of the current Guide
during their meeting on May 29-30, 2006
Revision History
Revision History
Revision History
PIC/S GMP Guide Part I
On Going Stability Program

should be
6.23. After marketing, the stability of the medicinal product
monitored according to a continuous appropriate
programme that will permit the detection of any stability issue (e.g.
changes in levels of impurities, or dissolution profile) associated with the
formulation in the marketed package.

6.24. The purpose of the on-going stability programme is to monitor the

product over its shelf life and to determine that the product remains, and can
be expected to remain, within specifications under the labelled storage
conditions.
PIC/S GMP Guide Part I
On Going Stability Program

6.25. This mainly applies to the medicinal product in the package in which it
is sold, but consideration should also be given to the inclusion in the
programme of bulk product. For example, when the bulk product is stored for
a long period before being packaged and/or shipped from a manufacturing
site to a packaging site, the impact on the stability of the packaged product
should be evaluated and studied under ambient conditions. In addition,
consideration should be given to intermediates that are stored and used over
prolonged periods. Stability studies on reconstituted product are performed
during product development and need Chapter 6 Quality control PE 009-12
(Part I) - 36 - 1 October 2015 not be monitored on an on-going basis.
However, when relevant, the stability of reconstituted product can also be
monitored.
PIC/S GMP Guide Part I
On Going Stability Program

6.26. The on-going stability programme should be described in a written

protocol following the general rules of Chapter 4 and results formalised as a
report. The equipment used for the on-going stability programme (stability
chambers among others) should be qualified and maintained following the
general rules of Chapter 3 and annex 15.
PIC/S GMP Guide Part I
On Going Stability Program

6.27. The protocol for an on-going stability programme should extend to the
end of the shelf life period and should include, but not be limited to, the
following parameters:
• number of batch(es) per strength and different batch sizes, if applicable
• relevant physical, chemical, microbiological and biological test methods
• acceptance criteria
• reference to test methods
• description of the container closure system(s)
• testing intervals (time points)
• description of the conditions of storage (standardised ICH conditions for
long term testing, consistent with the product labelling, should be used)
• other applicable parameters specific to the medicinal product.
PIC/S GMP Guide Part I
On Going Stability Program

6.28. The protocol for the on-going stability programme can be

different from that of the initial long-term stability study as submitted in
the marketing authorisation dossier provided that this is justified and
documented in the protocol (for example the frequency of testing, or
when updating to ICH recommendations).

6.29. The number of batches and frequency of testing should provide

a sufficient amount of data to allow for trend analysis. Unless
otherwise justified, at least one batch per year of product
manufactured in every strength and every primary packaging type, if
relevant, should be included in the stability programme (unless none
are produced during that year). For products where on-going stability
monitoring would normally require testing using animals and no
appropriate alternative, validated techniques are available, the
frequency of testing may take account of a risk-benefit approach. The
principle of bracketing and matrixing designs may be applied if
scientifically justified in the protocol.
PIC/S GMP Guide Part I
On Going Stability Program

6.30. In certain situations, additional batches should be included

in the on-going stability programme. For example, an on-going
stability study should be conducted after any significant change
or significant deviation to the process or package. Any
reworking, reprocessing or recovery operation should also be
considered for inclusion.

6.31. Results of on-going stability studies should be made

available to key personnel and, in particular, to the Authorised
Person(s). Where on-going stability studies are carried out at a
site other than the site of manufacture of the bulk or finished
product, there should be a written agreement between the
parties concerned. Results of on-going stability studies should
be available at the site of manufacture for review by the
competent authority.
PIC/S GMP Guide Part I
On Going Stability Program

6.32. Out of specification or significant atypical trends

should be investigated. Any confirmed out of specification
result, or significant negative trend, should be reported to
the relevant competent authorities. The possible impact on
batches on the market should be considered in accordance
with chapter 8 of the GMP Guide and in consultation with
the relevant competent authorities.

6.33. A summary of all the data generated, including any

interim conclusions on the programme, should be written
and maintained. This summary should be subjected to
periodic review.
PIC/S GMP Guide Part II
Stability Monitoring of APIs

11.50 A documented, on-going testing program should be

designed to monitor the stability characteristics of APIs, and the
results should be used to confirm appropriate storage conditions
and retest or expiry dates.

11.51 The test procedures used in stability testing should be

validated and be stability indicating.

11.52 Stability samples should be stored in containers that

simulate the market container. For example, if the API is
marketed in bags within fiber drums, stability samples can be
packaged in bags of the same material and in smallerscale
drums of similar or identical material composition to the market
drums.
PIC/S GMP Guide Part II
Stability Monitoring of APIs

11.53 Normally the first three commercial production

batches should be placed on the stability monitoring
program to confirm the retest or expiry date.
However, where data from previous studies show
that the API is expected to remain stable for at least
two years, fewer than three batches can be used.

11.54 Thereafter, at least one batch per year of API

manufactured (unless none is produced that year)
should be added to the stability monitoring program
and tested at least annually to confirm the stability.
PIC/S GMP Guide Part II
Stability Monitoring of APIs

11.55 For APIs with short shelf-lives, testing should

be done more frequently. For example, for those
biotechnological/biologic and other APIs with shelf-
lives of one year or less, stability samples should be
obtained and should be tested monthly for the first
three months, and at three month intervals after that.
When data exist that confirm that the stability of the
API is not compromised, elimination of specific test
intervals (e.g. 9 month testing) can be considered.

11.56 Where appropriate, the stability storage

conditions should be consistent with the ICH
References
http://www.fda.gov.ph/attachments/article/224762/PE%20009-
12%20GMP%20Guide%20(Intro).pdf

http://www.fda.gov.ph/attachments/article/224762/PE%20009-
12%20GMP%20Guide%20(Part%20I%20Basic%20Requirements%20fo
r%20Medicinal%20Products).pdf

http://www.fda.gov.ph/attachments/article/224762/PE%20009-
12%20GMP%20Guide%20(Part%20II%20Basic%20Requirements%20f
or%20APIs).pdf