Post Approval
Stability Studies
LEARNING OBJECTIVES
• Awareness of ICH / EMA / other Stability Guidelines
• Understand minimum requirements for Routine
Stability study of marketed products (for API, Drug
Product and Medical Device)
• Understand necessary studies/changes that impact
marketed product stability
ICH Guidelines - Stability
• Q1A(R2) - Stability Testing of New Drug Substances and Products
(Revision 2) (August 2003) = CPMP/ICH/2736/99 : Zones I and II
• Q1B – Photostability Testing of New Active Substances and Medicinal
Products (January 1998) = CPMP/ICH/279/95
• Q1C – Requirements for New Dosage Forms (January 1998) =
CPMP/ICH/280/95
• Q1D – Bracketing and Matrixing Designs for Stability Testing of Drug
Substances and Drug Products (August 2002) = CPMP/ICH/4104/00
• Q1E – Evaluation of Stability Data (August 2003) = CPMP/ICH/420/02)
• Q1F – Stability Data Package for Registration Applications in Climatic
Zones III and IV (August 2003) = CPMP/ICH/421/02 : Withdrawn on June
1st 2006.
• Q5C – Stability Testing of Biotechnological/Biological Products (July
1996) = CPMP/ICH/138/95
EMA Guidelines - Stability
• Stability Testing of Existing Active Substances and Related Finished
Products : CPMP/QWP/122/02, rev 1 (March 2004)
• Declaration of Storage Conditions :
– A : In the Product Information of Medicinal Products
– B : For Active Substances : CPMP/QWP/609/96/Rev 1 (October 2003)
(Annex to ICH Q1 A (R2) and to CPMP/QWP/122/02, rev 1)
• Stability Testing for Applications for Variations to a Marketing
Autorisation : CPMP/QWP/576/96 Rev 1 (01 December 2005)
• DRAFT : Stability Testing for Active Substances and Medicinal
Products manufactured in Climatic Zones III and IV to be marketed
in the EU : CPMP/QWP/6142/03 – Consultation (August 2004)
Additional Guidelines (1)
• EMA Guidelines
– Start of shelf-life of the finished dosage form (Annex to NFG on the
manufacture of the finished dosage form): CPMP/QWP/072/96 (December
2001)
• EU Commissions Guidelines
– Notice to applicants: Dossier requirements for Type 1A and type 1B
notifications – Volume 2C (June 2006)
• US FDA CDER 21 CFR Part 211.166
– Current Good Manufacturing Practice for Finished Pharmaceuticals-Stability
Testing
• US FDA CDER Guidance for Industry
– Changes to an Approved NDA or ANDA April 2004
Additional Guidelines (2)
• ASEAN Guideline on stability study of drug product, updated
version February 22, 2005 : Drug products : NCE, Generics and
Variations
• WHO Technical Report Series N° 863, 1996, Guidelines for
stability testing of pharmaceutical products containing well
established drug substances in conventional dosage forms,
revised by technical Report Series N° 908, p 13, 2003 and N°
937, p 12, 2006.
Additional Guidelines (3)
• WHO Working document QAS/06.179/Rev.2 August-September
2007 : Stability testing of active pharmaceutical ingredients and
pharmaceutical products.
– Close to ICH Q1A(R2) and EMA CPMP/QWP/122/02, rev 1
– New Chemical Entities and existing APIs and their related pharmaceutical
products, not applicable for biologicals
– Specific items : In-use stability, variations, ongoing stability studies
– Climatic Zones : I, II, III, IVA, IVB
– Climatic Zones defined for some countries (less WHO Eastern
Mediterranean Draft regional compared to Rev 1 April 2007)
• WHO Eastern Mediterranean Draft regional guidelines on stability
testing of active substances and pharmaceutical products, August
2006 : NCE, existing active substances and related pharmaceutical
products.
Additional Guidelines (4)
• Brazil : Guide for the Undertaking of Stability Studies :
Federative Republic of Brazil ; National Press, Official Gazette
of the Union Supplement to N°. 146 - Section 1 Brasilia - DF,
Monday, August 1st, 2005.
• Ministry of Health, National Agency of Health Surveillance,
Resolution - RE N°. 1, of July 29, 2005
– Guide for undertaking the stability tests of pharmaceutical products so
as to predict, determine or follow-up their validity term
– Long-term conditions : Zone IVB : general case 30°C ± 2°C 75% RH ± 5%
RH
Purpose – Stability Studies
• A marketed product stability program fulfils registration
commitments and ensures that marketed product is stable
(potent) until expiry date stamped on product label
• Post-approval stability testing is to verify that Active
Pharmaceutical Ingredients (API), Pharmaceutical Products
and Medical Devices comply during their retest period or
shelf life with the specifications defined in the Marketing
authorisation
Stability Study….
• Provides evidence on how the quality of an active
pharmaceutical product, medical device, or
pharmaceutical product (i.e. drug product) varies
with the time under the influence of a variety of
environmental factors such as temperature,
humidity and light and enables recommended
storage conditions, retest date/periods or shelf life
to be established.
Common Terminology (1)
• Long-term testing :
– Stability studies under the recommended storage condition for the
retest period or shelf-life approved for labelling
• Accelerated testing :
– Studies designed to increase the rate of chemical degradation or
physical change of active pharmaceutical product, medical device or
pharmaceutical product (I.e. drug product) by using exaggerated
storage conditions as part of the formal defined storage program
• Climatic Zone :
– Zones into which the world is divided based on the prevailing annual
climate conditions. Zone I is temperate. Zone II is subtropical and
Mediterranean with possible high humidity. Zone III is hot and dry.
Zone IVa is hot and humid. Zone IVb is hot and very humid.
Common Terminology (2)
• Date of Manufacturing :
– The first day of compounding for pharmaceutical products. It is the
date of the final production step for chemical substances
• Retest Date :
– The date after which samples of the API should be examined to ensure
that the material is still in compliance with the specification and thus
suitable for use in the manufacture of a given pharmaceutical product
• Shelf life :
– The time interval that a pharmaceutical product (i.e. drug product) or
medical device is expected to remain within the approved specification
provided that it is stored under the conditions defined on the label in
the proposed containers and closure
Common Terminology (3)
• Expiry date/Expiration date :
– The date placed on the container label of an API / pharmaceutical product
designating the time during which a batch of the API / product is expected to
remain within the established/approved shelf-life specification, if stored under
defined conditions, and after which it must not be used
• Bracketing :
– The design of stability schedule such that only samples on the extremes of certain
designs factors (e. g. strength, container size and/or fill) are tested at all time
points as in the full design. The design assumes that the stability of any
intermediate levels is represented by the facility of the extremes tested
• Matrixing :
– The design of a stability schedule that a selected subset of the total number of
possible samples for all factor combinations would be tested at a specified time
point
• T0 :
– Initiation of the stability study (i.e. samples put in the climatic chambers)
Routine Post Approval Stability
Testing
• Routine stability monitoring is performed to
confirm stability characteristics of tested materials
during the routine production :
– Verify the retest date/expiry date established for active
substances and shelf life/expiry date for drug products and
medical devices, demonstrating current product and
process is under control
– Stability studies on routine annual batch
Changes and Variations (1)
• Whenever a change to product, pack, process or site is made, that
may affect product stability (assessed by Change Control system
or stability failure investigation) stability testing is initiated to :
– Verify the established expiry period, including first 3 production batches
– Support change in the source of active substance/excipient for existing
product
– Support change to product, package, process for existing product
– Justify a bulk holding time
– Support site transfer for existing product
– Support a process/product deviation investigation
– Support reworking/reprocessing
– Support a change of storage conditions (for example to ICH conditions)
– Support extension of the initially established expiry period
Changes and Variations (2)
• The decision regarding the classification of
any change as a minor (Type IA and IB) or
major (Type II) change should be made on a
scientific basis and based upon the EC Notice
to Applicants Guideline
– With respect to the existing registered formula of
known stability profile.
Examples of Minor Changes – Little or
no impact on product stability (1)
• Minor changes in synthesis of drug substances where there is no
change in qualitative and quantitative impurity profile or in
physico-chemical properties i.e. particle size, apparent volume.
The active substance is not a biological substance and the
synthetic route remains the same
• Change in specification of an excipient. The change does not
concern adjuvant for vaccines or a biological excipient
• Change in test procedure for an excipient. The substance is not a
biological excipient
• Change in the specifications of the primary packaging of the
finished product
• Change in batch size of the finished product : up/down by a factor
of 10 times the size of the original approved batch. Normally
stability studies are requested when batch size is up/down scaled
more than 10 times (biological active substances excluded).
Examples of Minor Changes – Little or
no impact on product stability (2)
• Change to alternative equipment of the same
design and operating principles (a minor change in
the manufacturing process of the finished product
requires stability studies).
• Change in test procedures of drug product with no
change in specification (i.e., optimisation of
methods).
• Change in the dimensions of tablets, capsules,
suppositories or pessaries ; without change in the
quantitative composition and mean mass.
Examples of Major Changes – Likely to
impact on product stability (1)
• Any quantitative or qualitative excipient changes
• Change in the technical grade of an excipient i.e. particle size
• Change in manufacturer for drug substance
• Major changes in synthesis of drug substance (change in
qualitative or quantitative impurity profile)
• Changes in the excipient ranges of low solubility or low
permeability drugs.
Examples of Major Changes – Likely to
impact on product stability (2)
•
•
•
•
•
•
•
Change of storage conditions
Change in specifications of the drug product or API
Change in test procedures linked with a change in specification
Change in dimensions of a sustained release formulation
Major changes in manufacture of the drug product
Change from wet granulation to direct compression of dry powder
Site change to a contiguous facility on the same campus or change
of the manufacturing site to a different campus
• Change in batch size beyond 10 times the size of the original batch
• Change to equipment of different design and different operating
principles.
Responsibilities – Site
Management (1)
• Ensure procedures and systems for Stability Programs
including review and approval of stability protocols and
reports
• Ensure adequate storage, utilities, equipment, security
and personnel to perform stability programs
• With Manufacturing representative, select batches to
be put under stability including campaign production.
Responsibilities – Site Quality (2)
• To optimise resources select batches to be put in stability in the
event of multiple changes instead of putting all batches on
stability
• Rapidly react and initiate follow-up actions (with Quality Control)
in case of unusual observations : OOS or OOT during testing
• Ensure SOPs for Stability Programs are in place and are consistent
with company policies and other regulatory requirements
• Ensure pharmaceutical products manufactured, packaged or
distributed by (or for) the given site are put under stability
• Involved in the review and approval of potential changes to
product, manufacturing process or packaging that may impact on
product’s stability profile and shelf-life.
Responsibilities – Site Quality
Control (3)
• Written procedures for
– initiating/conducting stability programs
– Labelling samples for stability studies in an adequate
manner
– reporting/trending/archiving data
– maintenance/calibration of storage/testing equipment
• Organise periodical review of data and reporting trends that
may result in product failing to meet specifications during
retest period or shelf-life
Responsibilities – Laboratory
Manager/Analyst (4)
• Laboratory
– complete review of laboratory actions leading to
stability result and approve laboratory
investigations reports, retest plans, re-sampling
justification and plans, conclusion from failure
investigations
• Analyst
– identify OOS/atypical results (OOT) – report them
to laboratory management
General Points To Consider (1)
• Approved protocols for each study (Routine or post-approval
variations) in compliance with the zone in which the product
is marketed
• In the event the Manufacturing and Packaging operations
are performed at different sites, a decision must be taken as
to which site is responsible for routine post-approval
stability study
• Site Management/Quality must be immediately informed in
case of result failure : OOS/OOT.
General Points To Consider – Storage
Facility Control and Maintenance (2)
• Use Robust systems where possible, for example continuous
power supply : back-up generator, alarm, back-up climatic
chambers
• Prior to use, Storage Facilities mapped for temperature &
humidity with typical load pattern. Re-map when significant
changes to area or controls
• Storage Facilities calibrated regularly : temperature and humidity
• Procedures to continuously monitor temperature and humidity
– What actions in event of storage condition failure ?
– Record failures : Review and assess by senior stability person
– Deviations must be documented and require investigation(s)
• Keep Durable Records of storage conditions
– Archive 1 year minimum beyond expiration date of any products stored.
General Points To Consider –
Stability Protocol (3)
• Each approved protocol must contain :
– Purpose: objective of study
– Specifications: tests and associated acceptance limits/criteria
– Storage Conditions/Test Schedules: correlate condition with test interval
and test performed at that interval
– Sample Requirements: number of samples for each time point and for the
study as a whole
• Follow regulatory and product license requirements
• Approved protocols are binding
• Changes are discouraged - if necessary through approved change
control procedure
• Use stability indicating methods, in case of method change: new
method must be validated, and approved. Analytical results from
new methods should be proven through comparison to previous
results.
General Points To Consider –
Stability Protocol (4)
• Studies conducted on samples manufactured at the site; in
the event manufacturing, packaging or distribution
performed at different sites >> decision must be taken which
site is responsible for follow-up stability testing
• Studies on at least one lot per year
• High volume products (e.g. >50 batches per year) requires
studies on more than one batch per year
• All marketed products included in a stability program:
strength/packaging.
General Points To Consider –
Stability Protocol (5)
• Not every primary packaging presentation but the most
sensitive/vulnerable
• The use of « Bracketing » and/or « Matrixing » permitted
but must be justified
• Consideration must be given to storage conditions between
the time the sample is taken and the analysis is performed:
minimise degradation process
• Bulk storage, holding-times, time out of refrigeration or
freezing, storage of intermediates, in-use and transportation
stability, as appropriate must be studied.
General Points To Consider –
Stability Protocol (6)
• For initiation of stability study (T0) after date of
manufacturing: within 3 months
• For withdraw from storage : between 2 weeks of planned
time point and at the same time samples must be retrieved
just prior to analysis. If time point not met, samples kept in
climatic chambers and report bears actual retrieval and
testing dates
• For finishing analysis after having retrieved samples : within
30 calendars days (unless test duration is > 30 days), if
additional time is required, the original retrieved samples
must be stored at conditions that minimise the degradation
process.
General Points To Consider –
Criteria's to be Monitored (7)
• Change in Colour, Appearance of Product/Package (including
labelling)
• Potency and Purity at each time point – Impurity Profile /
Degradation impurities: Any new observed impurities ?*
• Pharmaceutical Properties, some examples :
– Disintegration/Dissolution for solids
– Dose Delivery/Unit Spray Content for Aerosols
*Refer to ICH NFG: Q3 A(R)
- Impurities in New Drug Substances (August 2002) = CPMP/ICH/2737/99;
Q3 B ( R )
- Impurities in New Drug Products (August 2003) = CPMP/ICH/2738/99 and
European Pharmacopoeia Monograph: “Substances for Pharmaceutical
Use” 01/2005
General Points To Consider –
Criteria's to be Monitored (8)
• Microbial contamination
• Parenterals : Sterility test, Pyrogens, Endotoxins (tested at
least at expiry date)
• Products normally stored upright
– consider additional orientations, for example change to
container/closure
• Photo-stability & Freeze-Thaw studies. These are usually not
performed for Follow-up or after variations
Note: Programs conducted in Final Market Primary Package for DP, API or Bulk
DP sold in large drums may be placed in smaller/equivalent containers for
stability studies, based on a justified rational.
General Points To Consider – Contract
Laboratories and Transfers (9)
• Satisfactory audit prior to any start of testing
• Analytical procedure (method) transfer successfully concluded
• In case of production transfer, routine post marketing stability
testing transferred to receiving site
• Stability program must be established as part of product transfer
process
• If manufacture is in the situation of terminating, stability program
must be continued to end of shelf life
• If a solid dosage form is produced at one site and packaged at
another, stability program may be reduced at one site if stability is
not critical and packaging materials and processes are equivalent.
General Points To Consider – Data
Review and Reporting (10)
• Quality management must review stability results at least
annually
• Trend analysis of data must be undertaken. Trends that
would predict a failure for product/medical device to meet
shelf life specifications is to be managed through a quality
alert reporting procedure
• OOS and OOT must be investigated according to the
corresponding procedure
• In case of a confirmed OOS, local requirements must be
considered for reporting to regulatory authorities.
General Points To Consider – Data
Review and Reporting (11)
•
•
•
•
•
All results presented in stability reports
Must be approved by senior stability personnel
Suitable quality for submission to regulatory authorities
Issued at each significant milestone of study
Contain conclusions and shelf-life recommendation
– Based upon full review of data and statistical analysis, as appropriate.
– See Guidance from ICH Q1E (Evaluation of Stability Data)
– Several statistical treatments possible - not specified here
• End with Stability Report Design
Example Stability Report Format
(1)
• I Cover & Approvals signatures
• II Introduction Purpose of study, products, packages, site and any
other information
• III References Protocol number, approval date and indication as to
whether the protocol is included in the corresponding (A)NDA.
• IV Results should be tabulated by lot/study
• V Analysis A. Statistical Analysis Regression Analysis (with tests for
similarity of slopes by strength, package and lot), as
appropriate any other Analysis.
B. Protocol Deviations*
*Note: all deviations from the protocol or acceptance criteria must
provide justification for accepting the deviation or out of specification
result where applicable.
Example Stability Report Format
(2)
• VI Conclusions, Study meets/fails acceptance criteria,
references to other supportive data/studies
• VII Recommendations, Study support and expiration date (of
xx months) and any other Recommendations.
Example Stability Report Format
(2)
• VI Conclusions, Study meets/fails acceptance criteria,
references to other supportive data/studies
• VII Recommendations, Study support and expiration date (of
xx months) and any other Recommendations.
Long Term Stability Storage
Conditions (1)
• Storage conditions
–
–
–
–
–
Zone I 25°C +/- 2°C / 45% RH +/- 5% RH
Zone II 25°C +/- 2°C / 60% RH +/- 5% RH
Zone III 30°C +/- 2°C / 35% RH +/- 5% RH
Zone IVa 30°C +/- 2°C / 65% RH +/- 5% RH
Zone IVb 30°C +/-2°C / 75% RH +/- 5% RH
• Temperature sensitive products (intended for storage in a
refrigerator) 5°C +/- 3°C
• Temperature sensitive products (intended for storage in a
freezer) - 20 °C +/- 5°C
• Products in semi permeable containers 25 °C +/- 2 °C / 40 %
RH +/- 5 % RH or 30 ° C +/- 2 °C / 35 % RH +/- 5 % RH
Long Term Stability Storage
Conditions (2)
• Relaxing measures:
– To keep the number of storage chambers for the respective
manufacturing site at a minimum necessary, studies
planned for Zone I might also be performed at Zone II
conditions (25 °C +/- 2 °C /60 % RH +/- 5 % RH)
• For products in impermeable containers,
relative humidity is not a relevant parameter.
Long Term Stability Storage Conditions
– Post Variation Studies (3)
• Accelerated Storage Conditions
– + 40° C ± 2ºC/ 75% RH ± 5 % RH
– For products intended for storage in a refrigerator: 25°C
+/- 2°C / 60 % RH +/- 5 % RH
– For products packaged in semi-permeable containers: 40
°C +/- 2 °C RH max 25 %
• See next slide for summary table on routine
stability monitoring and sampling and testing
requirements for qualifying changes.
Stability Sampling and Testing - Routine Monitoring
Minimum Sampling
Pharmaceutical Products and Testing
Category l
Frequency
Minimum
Sampling
Requirements
Pharmaceutical Products Category ll
Transferred Products to Sites and Products with
Variations - Category lll
Stability well-proven
All other products not
throughout shelf-life
in Category I or III
with no OOS for at least the
last three batches
tested for stability and no
change to the
manufacturing process for
these batches
1 Lot per year
1 Lot per year. A
second Lot may be put
under stability when
annual production
exceeds more than 50
batches
Refer to Table A on next
Refer to Table B
slide
Minor/Moderate
changes
Major Changes
Minimum of 1 lot or
Depending on local
regulatory
requirements
First 3 lots
3 Post – Approval
lots
T0, 3, 6, 9, 12, 18, 24,
30 *, 36 *, 48 *, 60 *End time point
Unless justified and
approved by local
authorities
Not applicable
T0, 3, 6
Unless justified and
approved by local
authorities
T0, 3, 6, 9, 12, 18,
24, 30 *, 36 *, 48*,
60 * -End time
point
Unless justified
and approved by
local authorities
T0, 3, 6
Long-Term
Stability Testing
Accelerated
Testing
Stability Sampling and Testing - Qualifying
Changes
Not applicable
Table A – Sampling and Testing
Frequency
Shelf Life (months)
12
18
24
36
48
60
T0
X
X
X
X
X
X
T6
X
T9
X
TIME POINTS (months)
T12
T18
T24
X
X
X
X
X
X
X
X
X
X
T36
T48
T60
X
X
X
= release or shelf life specification
X = mandatory time point with reduced risk based testing
permitted
= optional additional time point depending on earlier time point stability results
X
Table B – Sampling and Testing
Frequency
Shelf Life (months)
12
18
24
36
48
60
T0
X
X
X
X
X
X
T6
X
T9
X
TIME POINTS (months)
T12
T18
T24
X
X
X
X
X
X
X
X
X
X
X
T36
T48
T60
X
X
X
X
X
X
= release or shelf life specification
X = mandatory time point with reduced risk based testing
permitted
= optional additional time point depending on earlier time point stability results
Conclusion – Stability Studies (1)
• If a risk-based approach to stability is followed during
development, then the stability characteristics of an API and
drug product would be properly understood and mapped
– Although the resource and cost requirements of this approach may be
greater initially, it should ensure that product failures due to
unexpected stability results are avoided further in the product life
cycle.
• Adopting a science and risk-based approach, combined with
an accelerated predictive model leads to >>Less routine, non
value added studies during development and commercial
phases
– Facilitates in the continuous improvement of processes without the
need to wait for unnecessary long-term data before changes could be
implemented.
Thank You
Any Questions