Post on 28-Nov-2014
Pharmalytik©
Key Factors to Design Quality Stability Program for Drug Product and API
Kim Huynh-BaPHARMALYTIK
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OVERVIEW
• Stability role in the drug development process
• Review cGMP and ICH stability requirements
• Develop Global Stability Protocols
• Design stability program by Phases of Development
• Presentation will focus on small molecules.
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Goals of Stability Testing
• ACTIVE PHARMACEUTICAL INGREDIENT (API)– To establish a retest date for API
– Data to support setting API specifications
– Data to support submission of drug product
• PHARMACEUTICAL DRUG PRODUCT– Data to support setting specifications for drug product
– To establish a shelf-life for the commercial product
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Critical Role of Drug Stability• Quality must be established for identity, strength, quality and
purity (CFR 211.137) to assure Safety and Efficacy during its shelf life when stored under the intended labeled condition.
• Safety and Efficacy of drug product are established during development via clinical studies
• If drug product stability changes beyond established acceptance criteria, established safety and efficacy are no longer applicable.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– Potential new degradants of unknown toxicity
• Uncontrolled process → product investigation → product recalls• cGMP violations → consent decree → criminal prosecution
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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
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Factors affecting Drug Stability
• Stability of the API from storage
• Interaction between the API and excipient – Form. Dev.
• 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
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DRUG DEVELOPMENT PROCESS
Excipients
•API Stability•Process impurity
•Packaging interaction•Storage conditions•Storage configuration
•Drug Product Stability•Excipient compatibility•Formulation interaction
PACKAGING SELECTION
FORMULATIONDEVELOPMENT
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Drug Development Process
Years
TestPopulation
Purpose
SuccessRate
3.5
Lab andAnimal Studies
Safety, biological
activity and formulation
5,000 evaluated
DiscoveryPre-clinical
1.5
20 - 100healthy
volunteers
Safety and
Dosage
5 enter clinical trials
Phase I Phase II Phase III
EvaluateEffective-
ness,look for
side effects
Confirm effectiveness,
monitor adversereactions fromlong-term use
1,000 - 5,000patient
volunteers
100 - 500patient
volunteers
3.52
Clinical Trials
File IND
File NDA
Rev
iew
and
App
rova
l
Additionalpost-
marketingtesting
requiredby FDA
1
1.5
Phase IV
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Purpose of Stability Testing• The purpose of stability testing is to provide
evidence on how the quality of a drug substance or drug product varies with timeunder the influence of a variety of environmental factors such as temperature, humidity and light.
• Stability testing permits the establishment of recommended storage conditions, retest periods, and shelf-lives.
– ICH harmonized Tripartite Guideline for Stability Testing of New Drug Substances and Products [ICH Q1A]
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211.166 Stability Testing
• Stability program must be written and followed:
– (a) used in determining appropriate storage conditions and expiration date.
– Written program must include: Sample size and test 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.
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211.166 Stability Testing
• (b) 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.
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211.137 EXPIRATION DATING
(a) To assure that a drug product meets applicable standards of identity, strength, quality, and purity at the time of use, it shall bear an expiration date determined by appropriate stability testing described in Sec. 211.166.
(b) Expiration dates shall be related to any storage conditions stated on the labeling, as determined by stability studies described in Sec. 211.166.
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International Conference on Harmonization (ICH)
• Purpose: To provide a forum for dialogue between Health Authorities and Industry on the disparities with respect to requirements of US, Europe and Japan (Zone 1 & 2)
• Goal: To develop guidelines that are acceptable for regulatory review by US, Europe and Japan
• ICH Steering Committee: 6 Parties– PhRMa, FDA, – EFPIA, EU, – MHLW, JPMA– and IFPMA (non voting member)– Official Observers: Canada, WHO, EFTA– Interested Parties: Pharmacopeia, IGPA, WSMI
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5 Major Steps in ICH Process
STEP 1 STEP 2 STEP 3 STEP 4 STEP 5
ConsensusBuilding
By EWG ConsensusAgreed
by 6 parties
RegulatoryConsultation
AdoptionOf ICHGuideline
Implemen-tation
Harmonizing Stability Storage Conditions
Handbook of Stability Testing in Pharmaceutical Development: Regulations, Methodologies and Best PracticesK. Huynh-Ba (ed.), Springer, Springer, November 2008, Chapter 2.
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ICH Guidances•M4: Common Technical Document (CTD) for the Registration of Pharmaceuticals for Human Use (CTD) (October 2001);•Q1A(R2): Stability Testing of New Drug Substances and Products (November 2003);•Q1B Photostability Testing of New Drug Substances and Product (November 1996);•Q1C Stability Testing of New Dosage Forms (May 1997);•Q1D Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products (January 2003);•Q1E Evaluation of Stability Data (June 2004);•Q1F Stability Data Package for Registration Applications in Climatic Zones III and IV, Revision 1 (July 2004);
•Ref: US FDA, Guidance for Industry on Chemistry, Manufacturing, and Controls Informations; Withdrawal and Revision of Seven Guidances, Federal Register 71 (105), 31194-31195 (June 1, 2006) DOCID: fr01jn06-73
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ICH Storage Conditions
12 months- 20 ºC/ ambientLong TermFreezer
6 months25 ºC/60%RHAccelerated
12 months5 ºC/ ambientLong Term
Refrigerated
6 months40 ºC/75%RHAccelerated
6 months30 ºC/65%RHIntermediate*
12 months25 ºC/60%RHLong Term
RoomTemperature
Submission Requirement
Study ConditionStability StudiesIntendedStorageCondition
* Significant change
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Significant Change
5. Dissolution exceeding the acceptance criteria for 12 dosage units.
4. The pH exceeding its acceptance criteria; and
3. Failure to meet acceptance criteria for appearance and physical properties (e.g., color, phase separation, resuspendibility, delivery per actuation, caking, hardness); and as appropriate to the product type;
2. Any specified degradant exceeding its acceptance criteria
1. A 5 percent potency change from the initial assay value;
DrugProduct
Significant change is defined as failure to meet the specification.
API
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Global Climatic Zones
• Zone I: Temperate less than 20oC– e.g. Germany, Russia, Canada
• Zone II: Sub-tropical with possible high humidity– averaging 20.5-24oC
– e.g. France, Peru, Australia, USA
• Zone III: hot and dry– e.g. Botswana, Chad, Syria, Iraq
• Zone IV: hot and humid– averaging more than 24oC
– e.g. Taiwan, Singapore, India, parts of South America
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WHO Meetings• WHO Draft Guidance – Nov 2003
– Zone IV --long term testing at 30°C/65% RH
• Association of Southeast Asian Nations (A.S.E.A.N.)
Cambodia, Brunei, Indonesia, Laos, Malaysia, Philippines, Singapore, Thailand, Vietnam.
WHO Decision - 2005Split current Climatic Zone IV into
– IVA – long term testing at 30°C/65% RH– IVB – long term testing at 30°C/75% RH
Members decide of which condition
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Why?
• Storage conditions listed in ICH and WHO guidelines based on average values in 23 cities
• Conditions of other cities are more stressful in term of temperature and humidity not representative
• Poor storage conditions, especially in rural areas.• Average temperature and humidity is 27ºC and 79%RH• Recommend long term storage to be 30ºC/75% RH, and 40 ºC/75%
RH for accelerated condition – June 2004• This condition is also preferred by some South American countries
such as Brazil
• ASEAN prefers more stressful condition than 30°C/65% RH. Chosen condition reflects extremes rather than average as ICH.
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Typical Global Stability Protocol
DLOH5 C
XXXXXXXX25 C
60%RH
XXXXXXX(X)30 C
65%RH
XXXXXXX(X)(30 C
75%RH)
XXX40 C
75%RH
X50 C
(X)Photo
36mo24mo18mo12mo9mo6mo3mo2mo1moTZCond.
Handbook of Stability Testing in Pharmaceutical Development: Regulations, Methodologies and Best Practices, K. Huynh-Ba (ed.), Springer, Springer, November 2008
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Global Stability Summary
• Registration Storage Conditions– Long-term (ICH) 25C/60%RH
– Intermediate (ICH) 30C/65%RH (HOLD)
– Long-term (WHO) 30C/65%RH
– Long-term (ASEAN & Brazil) 30C/75%RH
– Accelerated (ICH & WHO) 40C/75%RH
• Other stress conditions– 30C/90%RH
– 50C
– 60C
• Ideally, a global stability program for all registrations of a drug product
– Photostability
– Freeze-thaw
– Thermal cycling
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Environmental Chambers
• Two basic types: Reach-In and Walk-In
Reach-in chambers can be a self-contained units with good profile control, but have limited space.
Walk-in chambers have more storage space but are more difficult to control and validate
All chamber units must have temperature and humidity control over a defined range with suitable tolerances to meet ICH specifications. Must have continuous monitoring of parameters to allow documentation of chamber integrity at all times.
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Key Factors of Stability Chambers
• Chamber should be calibrated to appropriate technical specs.• Chamber should be validated with profiling matrix.• Temperature and humidity should be recorded continuously.• SOPs for operation of chamber should be prepared and
controlled.• Units should have logbooks for maintenance and repairs.• Units should have secured access to prevent tampering.• If electronic information is collected, the system should be
compliant with 21CFR11 requirements.• Alarm and backup systems should be in place to detect power
failures and prevent station from crashing.• Procedures should be in place for man-made or natural
disasters.
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Selection of batches
Must commit to put up 3 production batches with same protocol
Stability Commitment
Same to proposed commercial packagingContainer Closure
Similar to those used in pre-clinical and clinical studies
Acceptance Criteria
Representative of Commercial ProductionManufacturing Process
3 batches/strength(2 pilot + 1 lab scale)
3 batches(pilot scale)
Selection of Batches
DRUG PRODUCTAPI
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Key Factors of Q1A(R2)
• Must use Validated Stability-Indicating analytical methods• Methods must cover physical, chemical, biological and microbiological attributes• Studies evaluated under thermal and elevated humidity to cover storage, shipment and subsequent use• Accelerated and intermediate used to evaluate impact of short-term excursions.• Acceptance criteria should include individual and total upper limits for impurities and degradation productsNo formal statistical analysis is needed if data show little
degradation or variability.
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ShelfShelf--Life ProjectionLife Projection•• The shelf life is the time point where the 95 % confidence interThe shelf life is the time point where the 95 % confidence interval for val for
the regression line crosses the specification.the regression line crosses the specification.
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Example 2 Example 2 -- One Batch One Batch
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Q1E examplesQ1E examples
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ShelfShelf--Life ProjectionLife Projection--Multiple batchesMultiple batches
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Multiple BatchesMultiple Batches
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Example Example -- Multiple BatchesMultiple Batches
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Important Dates of Stability Study
Batch Manufactured
Release Testing
Stability Scheduled Testing
Drug Product Expiry
Expiration Date(Study End Date)
ReleaseDate
Stability Pull DatesManufacturing
Date
Study Start Date
TZ Testing
Packaging Date
Stability Testing in Pharmaceutical Development Handbook: Regulations, Methodologies and Best Practices, K.Huynh-Ba, ed., Nov. 2008.
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Considerations for Generics•OGD believes that stability of drug products is best ensured through Quality by Design (QbD)
•OGD’s Question-based Review (QbR) covers quality by design
•Include stress testing studies or studies incorporated by DMF reference
•Stability data is still needed to verify quality product quality and establish a shelf-life consistent with that quality
•Three batches if it is a complex drug product
One batch
One batch
# of Batches
3 months(0, 1, 2, and 3 months)
40°C ± 2°C75% RH ± 5% RH
Accelerated
Additional data as it becomes available
25°C ± 2°C60% RH ± 5% RH
Long-term
Minimum data at submission
Storage ConditionStudy
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Considerations for OTC•Draft guidelines from CHPA available in March 2004 for OTC Drug Products in the U.S. (that are not regulated by an NDA/ANDA).•Draft guidelines for changes to OTCs (major, moderate, minor)•Reduce some stability burden especially for those with extensive experience and history and excellent safety profiles.
LT – 5 pointsAccel – at least 3 pts
LT – 8 pointsACC – 4 points
Testing Intervals
May beAt least 1 BatchPhotostability
Accelerated3 Months Data
Long Term & Accelerated12 Months Data
Expiry Dating
1/10th Scale (justification needed for smaller size)
2 at 1/10th scale3rd may be smaller
Batch Size
At least 13# Batches
CHPA SWG Guideline(for OTCs)
ICH Q1A(R2)(for NCEs)
Pharmalytik©
Design Stability Program by Phases
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Design Program by Phases
• Stability Program varies depending on the phase and clinical study it supports
• Stability Study Goals...– Identify problems early – Know your product– Minimize repeat study– Identify critical control attributes
• i.e., Particle size• Develop a stable commercial product• Maintain database--stability informatics• Establish systems to cycle back learning • Develop stability strategies to expedite product
development
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Pre-Phase I strategies...
• Identify problems early– Test drug substance stability at:
• 25 °C (sealed glass ampul (SGA))
• 25 °C/85%RH (open container)
• 40 °C (SGA)
• 40 °C/75%RH (open container)
• 40 °C plus 5% water
• 60 °C (SGA)
• 60 °C plus 5% water (w/w)
• ICH photostability
• twice ICH photostability
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Early Phase strategies...
• Know your product– Aqueous solubility
– pH-solubility profile
– Solubility in various solvents used in AMES
– Hygroscopicity
– Crystallinity (XRPD, Polarized light microscopy)
– Thermal Analysis (DSC, TGA)
– Excipient compatibility studies (start early Phase I)
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Phase I Strategies...• Goals
– Reduce cycle time
– Get into man fast
– Determine pK and tolerability
• Pick the best in a cluster nomination
• Select formulation to minimize development time
– Standard solid dosage formulations
– Powder in a bottle (PIB)
– Liquid filled gel caps
• Begin work on Phase II dosage form--solid, liquid, etc.
• Understand the stability of your product
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Powder in a Bottle (PIB)• Drug substance in a bottle
– Constitute at site as solution or suspension prior to oral administration to subjects
– Constitute with commercially available Vehicles--Simple Syrup; sodium lauryl sulfate (SLS), etc.
• Advantages:– Uses same methods as used for drug substance– Uses stability of drug substance to support product and
establish retest date– Demonstrates stability in solution and no interference
from excipients– Gives formulators opportunity to develop Phase II
dosage form in parallel
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Phase I/II Stability Protocol
XXXXX(X)X25 C
60%RH
XXXXX(X)(X)(30 C
65%RH)**
XX(X)X40 C
75%RH
X40 C/75%RH
(Exposed)
End of Study
12mo9mo6mo3mo2mo1moTZConditions
**30 C/65%RH if clinical study is done in Zone III/IV
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Phase II/III Stability Protocol
• Stability profile of clinical materials must be monitored
• Test stations– 25 °C/60%RH
– 30 °C/65%RH (if trial conducted in zone III and IV)
– 40 °C/75%RH (Open Dish, 2 wks, 1mo)
– 40 °C/75%RH
– ICH Photostability (Open Dish & in container)
• What packaging will be required– Is your product moisture, light or heat sensitive
– Desiccant needed/filler
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Phase II Strategies and Goals...
• Finalize formulation and process• Finalize drug substance process• Define market image (Product definition, Packaging)• Develop global stability protocol• Support clinical trials• Prepare for End-of-Phase II meeting
– Enough stability data to support matrixing or bracketing design if desired
– Microbiology testing needed? Moisture? Chiral purity• Scale-up/Optimization of process parameters
– Stability studies on product made at the extremes of process asdefined by experimental design
– Wet granulation/Compression force• Demo/scale-up batch
– On stability one to three months prior to start of Phase III
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Phase III Strategies...• Manufacture submission batches (representative of commercial
production)– 12 month stability by time of filing
– Cover zone III and IV and Japan
• Three batches per strength– 2 at least pilot-scale (NLT 10%) - >100,000 units
– 1 lab-scale (25,000-50,000 units)
• In the container and closure proposed for marketing
• Implement global stability protocol
• Outsource stability testing if needed
• Automate as possible
• Data to support setting specifications
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Typical Phase II/IIIStability Protocol
(x)Photo
XXXXXXXX25C
60%RH
DLOH30C
65%RH
XXXXXXXX(30C
75%RH)
XXX40C
75%RH
36mo(EOS)
24mo18mo12mo9mo6mo3mo2mo1moTZCond.
30C/75%RH if clinical study is done in Zone III/IV
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Stability Testing Recommended
1. ICH Photostability: Test 1st lot in open dish. Test immediate package on if significant change.
2. 30°C/65%RH : HOLD, to be tested if 40°C/75%RH meets ICH significant change criteria. If clinical study is done at Zone 3 or 4, test 30°C/65%RH at 9, 12, 24 and 36 or LPO.
4. X-ray powder diffraction: Test 1st lot at 25°C/60%RH (TZ, 12, 18, 24 and 36) and 40°C/75%RH (6 mo)
5. Chiral assay: Test 1st lot at 25°C/60%RH (TZ, 12, 18, 24 and 36)
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Global Protocol NDA/MAA Considerations
• Conforms to ICH and regional guidelines, especially storage conditions)
• Generate data to support registrations worldwide (all 4 climate zones)
• Global Packaging, Container/closure requirements, including regional specific packages
• Support registration of drug substance & drug product - Analytical Tests and Global Specifications
• Ideally, a global stability program for all registrations of a drug product
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Typical NDA/MAAStability Protocol
DLOH5 C
XXXXXXXX25 C
60%RH
DLOH30 C
65%RH
XXX40 C
75%RH
X50 C
(X)Photo
36mo24mo18mo12mo9mo6mo3mo2mo1moTZCond.
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Typical Global Protocol(For all 4 zones)
DLOH5 C
XXXXXXXX25 C
60%RH
XXXXXXX(X)30 C
65%RH
XXXXXXX(X)(30 C
75%RH)
XXX40 C
75%RH
X50 C
(X)Photo
36mo24mo18mo12mo9mo6mo3mo2mo1moTZCond.
Handbook of Stability Testing in Pharmaceutical Development: Regulations, Methodologies and Best Practices, K. Huynh-Ba (ed.), Springer, Springer, November 2008
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Testing Recommended
• ICH Photostability: open dish testing on 1st lot. • 5°C: Sufficient samples must be placed at this condition to allow for
testing at 4 timepoints.• 30°C/65%RH : HOLD, to be tested if 40°C/75%RH meets ICH
significant change criteria. • X-ray powder diffraction: Test first lot at 25°C/60%RH annually and
40°C/75%RH (6 mo)• Chiral assay: Test first lot at 25°C/60% every 6 months • Microbial bioburden: test at least one lot at 25°C/60%RH (TZ) unless
data supports not testing. If moisture is 2 x TZ and water activity is NLT 0.6, test at 25°C/60%RH every 6 months
• For liquid, extractable at TZ and EOS (plastic containers only) when package and label adhesives are defined for the marketed product.
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Special Storage Conditions
• Liquids in Semi-Permeable Containers
– Long-Term: 25oC/40±5%RH (Zone I/II) or
30oC/35±5%RH (all zones)
– Intermediate: 30oC/65±5%RH
– Accelerated: 40oC/NMT25%RH
a. or 25C/60RH and calculate wt. loss equiv. to 25C/40RH
b. if 30C/35RH is long-term condition, no intermediate condition is needed
c. Test one lot exposed at 40°C/NMT 25%RH for aqueous only; not needed for impermeable containers.
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Adverse Shipping Conditions
• Thermal Cycling– e.g., 40oC, 4 days, then 25oC/60%RH, 3 days
– Repeat cycle twice
– Perform full testing at end of complete cycling
– Helpful in addressing questions from marketing and sales
• Freeze-Thaw Cycling– e.g., -20oC, 4 days then 25oC/60%RH, 3 days
– Repeat cycle twice
– Perform full testing at end of complete cycling
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Additional Considerations
• Based on developmental info, add time points around expected expiry to improve confidence in shelf-life estimates
• If time permits, extend studies for longer shelf-life
• Climatic Zones III & IVa– Continue testing at 30oC/65%RH for establishing
shelf-life
• Continue 40oC/75%RH testing to 12 months
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Benefits of Global Stability Program
• Improve efficiency
– All tests are done at the same time
– All tests are conducted at the same site/lab
– Good use of testing resources
– Avoids repeat testing due to regional packages
– Reduce cycle time
– Improve consistency
– Improve quality
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Cycle Diagram
AnalyticalMethods
Protocols
SOPs
DataReports
Metrology
cGMP, ICH, Global
Stability Program
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Conclusion• Understand the Regulatory Requirements versus Scientific
Requirements
• Understand stability role in the drug development process
• Stability profile needs to be established for drug product to assure safety, efficacy and quality.
• Design strategy for stability study based on data of development batches
• Need to understand the product to design Formal stability studies
• Develop stability program and maximize efficiency
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STABILITY NETWORKS
• AAPS Stability Focus Group
• Pharmaceutical Stability Discussion Group
• Upcoming Meetings:– Stability Workshop, Bethesda, MD – Sep. 09
– AAPS Annual Meeting, Los Angeles, CA – Nov. 09
– EAS Annual Meeting, Somerset, NJ – Nov. 09
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References• “Handbook of Stability Testing in Pharmaceutical Development:
Regulations, Methodologies and Best Practices”, Kim Huynh-Ba (ed.), Springer Springer Science and Media PublishingScience and Media Publishing, available November 2008, ISBN: 978-0-387-85626-1 www.springer.com or www.amazon.com
• Molzon J. (2007), FDA, “Current International Harmonisation Efforts: Opportunities and Challenges - A Regulator's Perspective”.
• Kopp S. (2007), WHO, “Update on WHO Guidelines”.• Slamet L. (2007), National Agency of Drug and Food Control, Indonesia,
“Requirements for South East Asian Markets”.• Saleh A. (2007), WHO EMRO, “Regional Guidelines on Stability Testing of API
and Pharmaceutical Products for the Eastern Mediterranean Region”.• Zahn M. et al. (2006), 3RPharma “A risk-based approach to establish stability
testing conditions for tropical countries”, Journal of Pharmaceutical Sciences 95: 946-965 / Erratum 96: 2177 (2007)
• G. Buehler (2007), FDA OGD, “Regulatory Requirements for Stability Testing of Generics”.
• J. Needels & M. Seibel, Novartis & Procter Gamble, “Stability Design for Consumer Healthcare Products”.
• W. Grimm (1987), “Stability Testing of Drug Products”.
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THANK YOU!!!THANK YOU!!!
•Any question?
Kim Huynh-BaPHARMALYTIKKim.huynhba@pharmalytik.comwww.pharmalytik.com