applying asean stability requirements to legacy … asean stability requirements to legacy products...
TRANSCRIPT
Applying ASEAN Stability Requirements to Legacy Products
& Managing Specifications Across
Climatic Zones
Ketan Shah, PhD Director, Global Quality Control
Biogen Idec Inc., Cambridge, MA
2014 AAPS Annual Meeting and Exposition
Outline • Review of Climatic Zones and Harmonized Guidances
ICH
ASEAN
WHO
• Points to Consider in Applying new Guidance to
Legacy Products
• Specifications Management Across Climatic Zones
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Stability Climatic Zones (ICH)
3
Zone I - 21°C/45%RH (Temperate)
Zone II - 25°C/60%RH (Subtropical)
Zone III - 30°C/35%RH (Hot/Dry)
Zone IV - 30°C/65%RH (Hot/Humid)
II II
IV III
IV
IV
I
IV
II
Comparative Review for the Four
Primary Climatic Zones
Calculated Data Derived Storage
Conditions (for long-term studies)
Climatic Zone
°C °C MKT % RH °C % RH
I 20.0 20.0 42 21 45
II 21.6 22.0 52 25 60 III 26.4 27.9 35 30 35 IV 26.7 27.4 76 30 70
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1Based on: Grimm W. and Krummen K. Stability Testing in the EC,
Japan and the USA, 1993, 38.
Global Stability Evolution
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ICH Q1A Guideline issued
WHO defined climatic zones and adopted stability guidelines
1993
1996
• Many legacy products developed pre-ICH or ASEAN guidelines
• ASEAN Guidance Finalized. • Brazil adopted similar guidance as ASEAN
2005
2006
EU GMPs adopted FDA guidance withdrawn ICH Q1F withdrawn
• WHO Guidance Finalized.
2009
ICH Q1A(R2) ICH Q1F Guideline issued
2003 2013
ASEAN guidance revised
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ASEAN Map and Countries
• Indonesia
• Malaysia
• Philippines
• Singapore
• Thailand
• Brunei Darussalam
• Vietnam
• Laos
• Myanmar
• Cambodia
Stability Climatic Zones (WHO/ICH)
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Zone I - 21°C/45%RH (Temperate)
Zone II - 25°C/60%RH (Subtropical)
Zone III - 30°C/35%RH (Hot/Dry)
Zone IVA - 30°C/65%RH (Hot/Humid)
Zone IVB - 30°C/75%RH (Hot/x Humid)
II II
IV
ASEAN
III
IV IV
I
IV
II
IVB
Summary of ASEAN Guidance
Type of Study ASEAN ICH/WHO
General Case 30°C/75% RH – (LT)
40°C/75% RH – (A)
25°C/60% RH (Zone II - LT) 30°C/65% RH (Zone IVA - LT)
30°C/75% RH (Zone IVB - LT)
40°C/75% RH – (A)
Aqueous products in permeable containers
30°C/75% RH – (LT) 2005
30°C/35% RH – (LT) 2013
40°C/75% RH – (A)
25°C/40% RH (Zone II – LT) 30°C/35% RH (Zone IV – LT)
40°C/NMT25% RH – (A)
Products in impermeable containers
30°C/monitored RH – (LT)
40°C/monitored RH – (A)
25°C/monitor RH (Zone II - LT)
30°C/monitor RH (Zone IV - LT)
40°C/monitored RH – (A)
Refrigerated/Freezer products
Harmonized requirements across climatic zones
• ASEAN Guidelines: Issued Feb 2005, Implementation – Jan 2009, Revision – May 2013
LT – Long-term; A - Accelerated
Data Evaluation/Risk Assessment
• Do not start studies under a new condition “blindly”
• Conduct a product-by-product evaluation or
determine if certain products can be grouped
together.
• Look at the stability section included in the filing
that resulted in approvals in ASEAN markets
• Look at all stability data available, long-term data
under non-ASEAN conditions, accelerated data as
well as any special studies conducted
• Do a literature search to understand instabilities
associated with the compound and potential
modes of degradation
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Product
Stability
API intrinsic
properties
Formulation
Mfg.
Process
Primary
Package
Test Methods
Specs
Expiry Period
Factors Affecting Stability
Label
Storage
Stability Storage
Condition
Potential CAPA Options
• Reduce expiry period
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Expiry Period
Specs
Primary
Pkg
Stability Cond
Mfg.
Process
Formul
ation
• Widen with proper justification
• Design a more protective package
• Change stability condition/storage label (e.g., cold chain for a temp sensitive product)
• Improve manufacturing process/controls
• Reformulate to a more stable product
Label
Storage
Managing Specifications Across
Climatic Zones
• Test Attributes/Test Methods
• Specifications (Release/Stability)
• Expiry Period/Label Storage Conditions
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Test Attributes/Methods
• File same test methods across climatic zones o If test methods are same, relatively easy to manage different
specifications
• If different tests/methods are filed in different
markets….two potential choices o Test all product batches to cover all tests (Global Specs concept) Provides maximum supply chain flexibility
o Test batches specific to market/regional specs for release (Regional Specs concept) Provides partial flexibility as supply
chain route determined upfront
• How do you manage implementation of method
changes globally? o Run duplicate methods until filings are updated?
o Justify to only run the “better” method?
o Other ideas?
• `
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Specifications
• Global specification, a myth or reality?
• Prepare internal systems to manage different spec
versions o May test and manage to tightest specs (possible for a “global” product)
o LIMS or equivalent data management system for country/regional specific
reporting
o ERP system for inventory management
o Regulatory system for tracking changes/approvals
• Compendial specs are not global o Some Zone III/IV markets refer to USP or EP specs for reference, but this
may not be appropriate, especially for degradation products specs
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Expiry/Label Storage Conditions
• Different expiry may be claimed based on
differences in stability profile across different
climatic zones (Zone II v/s Zone IVB)
• Labeling requirements also vary across different
countries/regions
• USP/EU/WHO labeling guidance can be used as
reference
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Label Storage Guidance Label Interpretation…
Store in a Refrigerator
(2 to 8 °C)
Excursions between 0 and 15 °C permitted
Calculated mean kinetic temperature not more than 8 °C
Transient spikes up to 25 °C may be permitted …supported by
stability data….
Store at CRT (per USP)
Store below 25 °C (per EU or
WHO labeling guidance)
Excursions between 15 and 30 °C permitted
Calculated mean kinetic temperature not more than 25 °C
Transient spikes up to 40 °C permitted and spikes above 40 °C
may be permitted ... supported by data
Store below 30 °C (per EU
or WHO labeling guidance)
Calculated mean kinetic temperature not more than 30 °C
Transient spikes up to 40 °C permitted and spikes above 40 °C
may be permitted ... supported by data
Precautionary Labels
Protect from freezing
Store in a cool, dry place
Other specific labels
Product should not be exposed to temperature below 0 °C
Store product between 8 – 15 °C and less than 40% RH
e.g., Avoid exposure to temperatures above 40 °C