Stability
Q1(R2)
Role Of Stability
• Safety and efficacy of drug product are established during
development via clinical studies
• Quality is established for identify, strength, quality and purity
• If drug product stability changes beyond established acceptance
criteria, established safety and efficacy are no longer applicable.
• Change of Drug Stability would risk patient safety
– Quality of finished products decrease
– Potential sub-potent or over-dose products
– Potential toxic unknown impurities
• Uncontrolled process → product investigation → product recalls
• cGMP violations → consent decree → criminal prosecution
DRUG DEVELLOPMENTT PROCESS
Factors affecting Drug Stability
• Stability of the Active Pharmaceutical Ingredient (API) from storage
• Interaction between the API and excipient
Formulation Development
• Selection of dosage form
• Manufacturing process of drug product
• Selection of container closure packaging system
• Effect of storage (temperature, humidity and light)
• Selection of marketing image
• Handling of the finished products
Purpose of Stability Testing
• The purpose of stability testing is to provide evidence on howthe quality of a drug substance or drug product varies with timeunder the influence of a variety of environmental factors such astemperature, humidity and light.
• Stability testing permits the establishment of
recommended storage conditions, retest periods, and
shelf-lives.
Drug Product Stability
• Stability characteristics of API or Drug Product is a critical
quality attribute of pharmaceutical product
• Stability Studies are used to:
– Establish how product changes over time under critical
environmental factors (temperature, heat and light)
– Determine appropriate product specifications
– Select marketing container closure system
– Determine appropriate storage conditions
– Justification of expiry of commercial product
– Provide necessary medical supplies
Stability Protocol
Stability program must be written and followed:
– Used in determining appropriate storage
conditions and expiration date.
– Written program must include: Sample size andtest
intervals, Storage conditions for samples,
– Reliable, meaningful, and specific test methods,
– Testing of drug product in marketed container,
– Testing of drug product for reconstitution at
dispensing time and reconstituted time.
Stability Protocol
An adequate number of batches must be tested to
determine an appropriate expiration date. A record of
such data must be maintained.
– Accelerated studies, combined with basic stability
information on the components, drug products, and
container-closure system, may be used to support
tentative expiration dates.
– Full shelf-life studies, if not available, are being
conducted.
Stability Q1(R2)Stability Q1(R2)
• ICH condition contributing 80% of pharmaceutical market
• Outlines minimum stability data package for new drug application.
It is not intended for INDs, ANDAs or sNDAs.
• Harmonizes stability requirement for marketing application in EU,
Japan and US. Other countries adopt with some modifications.
• Must use Validated Stability-Indicating analytical methods
• Methods must cover physical, chemical, biological and
microbiological attributes
.
Stability Q1(R2)
•Studies evaluated under thermal and elevatedhumidity to cover storage, shipment andsubsequent use
• Accelerated and intermediate used to evaluateimpact of short-term excursions.
• Acceptance criteria should include individualand total upper limits for impurities anddegradation products
•No formal statistical analysis is needed if datashow little degradation or variability.
API
Significant change is defined as failure to meet thespecification.
Drug Product
- 5 percent potency change from the initial assay value;
-Any specified degradant exceeding its acceptance criteria
-Failure to meet acceptance criteria for appearance andphysical properties (e.g., color, phase separation,resuspendibility, delivery per actuation, caking,hardness); and as appropriate to the product type;
-The pH exceeding its acceptance criteria; and Dissolutionexceeding the acceptance criteria for 12 dosage units.
Photostability:
Two types of studies, exposure is cumulative from the light sources
• Forced degradation study to generate potential degradation products
– 2 X exposure to UV and fluorescent sources
• Confirmatory study to confirm product and package performance
– NLT 1.2 million lux hours + 200 watts/hrs per sq. meter
Light Sources:
– Option 1
• Dual output light sources, such as D65/ID65
• Simulates artificial day light fluorescent lamp
• Use Xenon or Metal Halide
– Option 2
• Tandem exposure to single light source types
• Cool white fluorescent lamp + near UV fluorescent lamp (320-400 nm)
• Accumulate exposure under one, then the other
Bracketing:
• Used for packaging extremes
• Assume that the intermediates are represented by theextremes
• For a range of strengths, strengths must be identical orvery closely related in composition
• Can be applied to different container sizes or fills ofsame packaging system
• Bracketing design is NOT appropriate if extremes arenot demonstrated.
Matrixing:
• Define full design and reduced design (withexamples)
• Assume that the stability of each subset ofsamples tested represent
the stability of all samples at a given time point
• Define what is needed for justification
• Covering different batches, different strengths,different sizes of the
same container and closure, and, possibly, insome cases, different
container/closure systems….”
Design Program by Phase
• Stability Program varies depending on the phaseand
clinical study it supports
• Stability Study Goals...
– Identify problems early
– Know your product
– Minimize repeat study
– Identify critical control attributes• i.e., Particlesize
• Develop a stable commercial product
• Maintain database--stability informatics
• Establish systems to cycle back learning
• Develop stability strategies to expedite productdevelopment
Phase II & III
• Stability profile of clinical materials must be monitored
• Test stations
– 25 °C/60%RH
– 30 °C/75%RH (if trial conducted in zone III and IV)
– 40 °C/75%RH (Open Dish 1M)
– 40 °C/75%RH
– ICH Photostability
• What packaging will be required
– Is your product moisture, light or heat sensitive
– Desiccant needed/filler
Special storage conditions
• For liquids in semi-permeable package
– Long term: 25 oC/40%RH (Zone I/II)
Or 30 oC/35%RH (all zones)
– Intermediate: 30 oC/65%RH
– Accelerated: 40 oC/<25%RH and 40 ºC/75%RH
• To support adverse shipping and unusual storage of samples
(liquid)
– Freeze Thaw Cycling (-10 ºC to -20 ºC four days, 25 ºC or
25 ºC/60%RH for three days)
– Thermal Cycling (40 ºC four days, equilibrate to 25 ºC and
then 5 ºC for three days)
Analytical Methods
• Analytical methods must be validated for its
intended purpose.
• Analytical methods are needed for active ingredient,degradation products and other component of interest(211.166)
• Stability methods must be stability indicating
ICH Guidelines
Q1AR2…”The testing should cover, as appropriate, the
physical, chemical, biological and microbiological
attributes, preservative content, and functionality tests
(e.g for a dose delivery system). Analytical procedures
should be fully validated and stability indicating.”
Q2A… “Validated analytical procedures should be
used, irrespective of whether they are for in-process,
release, acceptance, or stability testing”.
ICH Guidelines
• Q3B: “Analytical methods should bevalidated to demonstrate that impuritiesunique to the new drug substance do notinterfere with or are separated fromspecified and unspecified degradationproducts in the drug product.”
ICH Guidelines
Q2A
“Stress studies (e.g. products of acid and base hydrolysis,
thermal degradation, photolysis, oxidation) for the drug substance and
for the active ingredient in the drug product should be provided to
demonstrate the specificity of the assay and analytical procedures for
impurities. “
• Goals
– Generate typical degradation products which may be expected on
stability at sufficient levels to allow identification
– Avoid secondary degradation
– Target range is 5-20 % loss of active as judged by assay relative to
an undegraded sample
– Look for purity and mass balance
Storage Conditions
Global storage conditions :
Selection of batches :
Q1A R2 -- API Stress Testing
Stress testing is required
– To understand the drug substance stability
– To establish degradation pathways
– To validate the stability indicating power of the analytical proceduresused.
– To support the severe conditions that may be encountered duringdistribution.
• Use single batch of material
– at temperature above the accelerated temperature (50 ºC, 60 ºC)
– humidity (e.g., 75 %RH or greater),
– oxidation and photolysis on the drug substance across a wide rangeof pH values
when in solution or suspension.
– Photostability testing should be an integral part of stress testing (ICHQ1B)
Q1A R2 -- API Stress Testing
• Study depend on the individual drug substance and typeof drug product. Some degradation pathways can becomplex and that, under forcingconditions,decomposition products may be observed thatare unlikely to be formed under accelerated or long-termtesting.
• Useful in developing and validating suitable analyticalmethods, but it may not always be necessary to examinespecifically for all degradation products if it has been
demonstrated that in practice these are not formed.
• Results from these studies are part of regulatorysubmission.
Typical Forced Degradation DesignDrug Substance
– Solid State:
• Heat: 60 ºC for up to 1 month
• Photostability: twice ICH requirements
– Solution State: depending on solubility
• Acid: 0.1-1N HCl to 2 weeks and to 60 ºC
• Base: 0.1-1N NaOH to 2 weeks and to 60 ºC
• Peroxide: 3% of H2O2 to 24 hours and to 40 ºC
• Photostability: twice ICH requirements
Typical Forced Degradation DesignDrug Product
• Drug Product:
– Heat: 60 ºC for up to 1 month
– Photostability: twice ICH requirements
– Using placebo as control
• For combination product (multiple active ingredients)
– Stress should be done for API individually and also in thepresence of the other API (s).
Potential Impurities
Impurities for APIs and Excipients:
• synthesis precursors
• synthesis bi-products
• residual solvents
• catalysts
• decomposition
• and other impurities
Impurities for Drug Products:
• degradations products
• extractables
• residual solvents
• unknown substances
Conclusion
• Stability is a critical quality attribute of the API and the
Drug Product
• Stability profile needs to be established for drug product
to assure safety, efficacy and quality.
• Understand key concepts to develop stability indicating
methods.
• Understand the Regulatory Requirements versus
Scientific Knowledge.
• Understand regional versus global concerns to develop
stability program
• Design strategy for stability study based on data of
development batches
• Review cGMPs violations and regulatory observations
• Develop stability program and maximize efficiency
DEFINITION
STABILITY
“The capacity off a drug product/substance to remain within
specifications established to ensure its system, identity,
strength, purity & quality”
The purpose off stability testing is to provide evidence on
how the quality off a drug substance or product varies with
time under the influence off a variety off environment factor.
– Temperature, humidity, light and to set up retest period
for the drug substance or a shelf-life for the drug product
and recommended storage conditions.
ICH Drug Stability Test Drug Stability Test
Requirements
•Scientific in approach
•Provide clear mandate to users
•Call for good infrastructure and investment in stabilitytesting
HOW TO GO ABOUT STABILITY STUDY
ICH
International Conference on
Harmonization of Technical
Requirements for Registration of Pharmaceuticals forHuman use.
ICH - A TRIPARTITE AGREEMENT
17 countries in three regions
The world biggest pool for production and
consumption of pharmaceuticals
Legal status of guidelines
Most of the guidelines havebecome part of the local
regulations in US , Europe and
Japan
THE ZONE CONCEPT
Distribution of world into
Four different zones
FOUR ZONES
