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

2

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

4

1Based on: Grimm W. and Krummen K. Stability Testing in the EC,

Japan and the USA, 1993, 38.

Global Stability Evolution

5

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EU GMPs adopted FDA guidance withdrawn ICH Q1F withdrawn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

6

ASEAN Map and Countries

• Indonesia

• Malaysia

• Philippines

• Singapore

• Thailand

• Brunei Darussalam

• Vietnam

• Laos

• Myanmar

• Cambodia

Stability Climatic Zones (WHO/ICH)

7

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

How Do You Manage Impact of

Emerging Stability Requirements

on Legacy Products?

9

ASEAN Stability Study Decision Chart

10

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

11

12

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

13

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

14

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?

• `

15

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

16

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

17

18

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

19