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Key Factors to Design Quality Stability Program for Drug Product and API



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

To establish a retest date for API Data to support setting API specifications Data to support submission of 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studies If drug product stability changes beyond established acceptance criteria, established safety and efficacy are no longer applicable.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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Excipients Drug Product Stability Excipient compatibility Formulation interaction



API Stability Process impurity


Packaging interaction Storage conditions Storage configuration

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Drug Development Process

Discovery Pre-clinical Years 3.5
Lab and Animal Studies

Phase I 1.5

Clinical Trials Phase III Phase II 2 3.5

1,000 - 5,000 patient volunteers Confirm effectiveness, monitor adverse reactions from long-term use

Phase IV 1.5 Review and Approval 1 File NDA

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Test Population

20 - 100 100 - 500 patient healthy volunteers volunteers Evaluate Effectiveness, look for side effects


Safety, biological Safety and activity and formulation Dosage

Additional postmarketing testing required by FDA

Success Rate

5,000 evaluated File IND

5 enter clinical trials

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 time under 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] AAPS_0409: 9


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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(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

Harmonizing Stability Storage Conditions

Consensus Building By EWG

Regulatory Consultation Consensus Agreed by 6 parties Adoption Of ICH Guideline


Handbook of Stability Testing in Pharmaceutical Development: Regulations, Methodologies and Best Practices K. Huynh-Ba (ed.), 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

Intended Storage Condition Stability Studies Long Term Room Temperature Intermediate* Accelerated Long Term Refrigerated Accelerated Freezer Long Term 25 C/60%RH - 20 C/ ambient 6 months 12 months Study Condition 25 C/60%RH 30 C/65%RH 40 C/75%RH 5 C/ ambient Submission Requirement 12 months 6 months 6 months 12 months

* Significant change Pharmalytik

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Significant Change
API Significant change is defined as failure to meet the specification. 1. A 5 percent potency change from the initial assay value; 2. Any specified degradant exceeding its acceptance criteria Drug Product 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; 4. The pH exceeding its acceptance criteria; and 5. Dissolution exceeding the acceptance criteria for 12 dosage units.
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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 30C/65% RH

Association of Southeast Asian Nations (A.S.E.A.N.) Cambodia, Brunei, Indonesia, Laos, Malaysia, Philippines, Singapore, Thailand, Vietnam. WHO Decision - 2005 Split current Climatic Zone IV into
IVA long term testing at 30C/65% RH IVB long term testing at 30C/75% RH Members decide of which condition
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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 27C and 79%RH Recommend long term storage to be 30C/75% RH, and 40 C/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 30C/65% RH. Chosen condition reflects extremes rather than average as ICH.
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Typical Global Stability Protocol

Cond. 25 C 60%RH 30 C 65%RH (30 C 75%RH) 40 C 75%RH 50 C Photo 5C (X) H O L D TZ X (X) (X) X 1mo 2mo 3mo X X X X X 6mo X X X X 9mo X X X 12mo X X X 18mo X X X 24mo X X X 36mo X X X

Handbook of Stability Testing in Pharmaceutical Development: Regulations, Methodologies and Best Practices, K. Huynh-Ba (ed.), Springer, November 2008


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Global Stability Summary

Registration Storage Conditions
Long-term (ICH) Intermediate (ICH) Long-term (WHO) Long-term (ASEAN & Brazil) Accelerated (ICH & WHO) 25C/60%RH 30C/65%RH (HOLD) 30C/65%RH 30C/75%RH 40C/75%RH Photostability Freeze-thaw Thermal cycling

Other stress conditions

30C/90%RH 50C 60C

Ideally, a global stability program for all registrations of a drug product Pharmalytik

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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
Selection of Batches Manufacturing Process Acceptance Criteria Container Closure Stability Commitment

3 batches/strength (2 pilot + 1 lab scale)

3 batches (pilot scale)

Representative of Commercial Production Similar to those used in pre-clinical and clinical studies Same to proposed commercial packaging Must commit to put up 3 production batches with same protocol
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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 products No formal statistical analysis is needed if data show little degradation or variability.
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Shelf-Life Projection
The shelf life is the time point where the 95 % confidence interval for interval the regression line crosses the specification.


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Example 2 - One Batch


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Q1E examples


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Shelf-Life Projection-Multiple batches


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Multiple Batches


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Example - Multiple Batches


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Important Dates of Stability Study

Packaging Date Manufacturing Date

Study Start Date Stability Pull Dates

Expiration Date (Study End Date)

Release Date

Batch Manufactured Release Testing

TZ Testing Stability Scheduled Testing

Drug Product Expiry

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) OGDs 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
Study Long-term Accelerated Storage Condition 25C 2C 60% RH 5% RH 40C 2C 75% RH 5% RH Minimum data at submission Additional data as it becomes available 3 months (0, 1, 2, and 3 months) # of Batches One batch One batch


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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.
ICH Q1A(R2) (for NCEs) # Batches Batch Size 3 2 at 1/10th scale 3rd may be smaller Testing Intervals LT 8 points ACC 4 points Photostability Expiry Dating At least 1 Batch Long Term & Accelerated 12 Months Data CHPA SWG Guideline (for OTCs) At least 1 1/10th Scale (justification needed for smaller size) LT 5 points Accel at least 3 pts May be Accelerated 3 Months Data AAPS_0409: 35


Design Stability Program by Phases


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

Conditions 25 C 60%RH (30 C 65%RH)** 40 C 75%RH 40 C/75%RH (Exposed) TZ X (X) X X 1mo 2mo (X) (X) (X) 3mo X X X 6mo X X X 9mo X X 12mo X X End of Study X X

**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

Scale-up/Optimization of process parameters

Enough stability data to support matrixing or bracketing design if desired Microbiology testing needed? Moisture? Chiral purity Stability studies on product made at the extremes of process as defined by experimental design Wet granulation/Compression force On stability one to three months prior to start of Phase III
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Demo/scale-up batch


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/III Stability Protocol

Cond. 25C 60%RH 30C 65%RH (30C 75%RH) 40C 75%RH Photo X X (x) TZ X H O 1mo 2mo 3mo X L X X 6mo X D X X X X X X X 9mo X 12mo X 18mo X 24mo X 36mo (EOS) X

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. 30C/65%RH : HOLD, to be tested if 40C/75%RH meets ICH significant change criteria. If clinical study is done at Zone 3 or 4, test 30C/65%RH at 9, 12, 24 and 36 or LPO. 4. X-ray powder diffraction: Test 1st lot at 25C/60%RH (TZ, 12, 18, 24 and 36) and 40C/75%RH (6 mo) 5. Chiral assay: Test 1st lot at 25C/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/MAA Stability Protocol

Cond. 25 C 60%RH 30 C 65%RH 40 C 75%RH 50 C Photo 5C (X) H O L D TZ X H X O 1mo 2mo 3mo X L X X 6mo X D X 9mo X 12mo X 18mo X 24mo X 36mo X


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Typical Global Protocol (For all 4 zones)

Cond. 25 C 60%RH 30 C 65%RH (30 C 75%RH) 40 C 75%RH 50 C Photo 5C (X) H O L D TZ X (X) (X) X 1mo 2mo 3mo X X X X X 6mo X X X X 9mo X X X 12mo X X X 18mo X X X 24mo X X X 36mo X X X

Handbook of Stability Testing in Pharmaceutical Development: Regulations, Methodologies and Best Practices, K. Huynh-Ba (ed.), Springer, November 2008


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Testing Recommended
ICH Photostability: open dish testing on 1st lot. 5C: Sufficient samples must be placed at this condition to allow for testing at 4 timepoints. 30C/65%RH : HOLD, to be tested if 40C/75%RH meets ICH significant change criteria. X-ray powder diffraction: Test first lot at 25C/60%RH annually and 40C/75%RH (6 mo) Chiral assay: Test first lot at 25C/60% every 6 months Microbial bioburden: test at least one lot at 25C/60%RH (TZ) unless data supports not testing. If moisture is 2 x TZ and water activity is NLT 0.6, test at 25C/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/405%RH (Zone I/II) or 30oC/355%RH (all zones) Intermediate: 30oC/655%RH Accelerated:
a. b. c.


or 25C/60RH and calculate wt. loss equiv. to 25C/40RH if 30C/35RH is long-term condition, no intermediate condition is needed Test one lot exposed at 40C/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
cGMP, ICH, Global Protocols Analytical Methods


Stability Program
Data Reports Metrology


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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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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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Handbook of Stability Testing in Pharmaceutical Development: Regulations, Methodologies and Best Practices, Kim Huynh-Ba (ed.), Springer Science and Media Publishing, available November 2008, ISBN: 978-0-387-85626-1 Publishing or
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!!! Any question?



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