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Pharmalytik
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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Uncontrolled process product investigation product recalls cGMP violations consent decree criminal prosecution
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FORMULATION DEVELOPMENT
PACKAGING SELECTION
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Phase I 1.5
Test Population
20 - 100 100 - 500 patient healthy volunteers volunteers Evaluate Effectiveness, look for side effects
Purpose
Success Rate
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Implementation
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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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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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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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 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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Handbook of Stability Testing in Pharmaceutical Development: Regulations, Methodologies and Best Practices, K. Huynh-Ba (ed.), Springer, November 2008
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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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Selection of batches
API
Selection of Batches Manufacturing Process Acceptance Criteria Container Closure Stability Commitment
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DRUG PRODUCT
3 batches/strength (2 pilot + 1 lab 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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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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Q1E examples
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Multiple Batches
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Release Date
Stability Testing in Pharmaceutical Development Handbook: Regulations, Methodologies and Best Practices, K.Huynh-Ba, ed., Nov. 2008.
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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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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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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
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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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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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40oC/NMT25%RH
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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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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Cycle Diagram
cGMP, ICH, Global Protocols Analytical Methods
SOPs
Stability Program
Data Reports Metrology
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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 Science and Media Publishing, available November 2008, ISBN: 978-0-387-85626-1 Publishing 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.
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