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Conducting Stability Studies - Recent Changes To Climatic Zone IV

This document discusses recent changes to stability testing guidelines for Climatic Zone IV regions, which include hot, humid countries. Specifically: 1) Stability testing guidelines were amended to reflect storage conditions of 30°C/65% RH for Zone IVa regions and 30°C/75% RH for Zone IVb, providing a larger safety margin for products in these areas. 2) Climatic zones help determine appropriate storage conditions for stability testing by simulating real storage and distribution conditions from manufacturing to end use. 3) Stability testing ensures drug quality is maintained over time under various environmental factors like temperature, humidity and light. It establishes a re-test or shelf-life period and recommended

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100% found this document useful (1 vote)
470 views2 pages

Conducting Stability Studies - Recent Changes To Climatic Zone IV

This document discusses recent changes to stability testing guidelines for Climatic Zone IV regions, which include hot, humid countries. Specifically: 1) Stability testing guidelines were amended to reflect storage conditions of 30°C/65% RH for Zone IVa regions and 30°C/75% RH for Zone IVb, providing a larger safety margin for products in these areas. 2) Climatic zones help determine appropriate storage conditions for stability testing by simulating real storage and distribution conditions from manufacturing to end use. 3) Stability testing ensures drug quality is maintained over time under various environmental factors like temperature, humidity and light. It establishes a re-test or shelf-life period and recommended

Uploaded by

Haider Ali Khan
Copyright
© Attribution Non-Commercial (BY-NC)
We take content rights seriously. If you suspect this is your content, claim it here.
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Article

Conducting Stability Studies – Recent Changes to


Climatic Zone IV
Ulrich Markens*
Regional Head Asia-Pacific, SGS Life Science Services

Stability testing is a routine procedure performed on drug substances and drug products to provide evidence on how the quality of a
drug varies with time under the influence of a variety of parameters. Environmental factors such as temperature, humidity and light
can potentially affect product quality and require establishing a re-test period for the drug substance or a shelf-life for the drug
product and recommended storage conditions.

Any physical, chemical or micro- In early stages, stability studies are production process changes. Retained
biological change in the product potentially conducted on the API to gather information samples can be tested alongside returned
impact the efficiency and integrity of the final about physical and chemical properties samples to determine whether the root cause
product and may therefore directly or (solubility profile, hydroscopicity, thermal - of the problem was manufacturing or storage
indirectly impact patients’ health. There are and chemical stability) and to determine a related.
three major types of “changes”: preliminary re-test period and storage
conditions. Accelerated stability testing can Climatic Zones
z Physical changes, which might effect be used as a “worst case” evaluation to
the appearance, melting point, clarity uncover the kinds of degradation products A very important point in conducting
and color of solution, water, crystal potentially found after long-term storage. stability studies are the storage conditions.
modification (polymorphism) or particle Gentle conditions (recommended for long- They should simulate the conditions under
size term storage) and slightly elevated which the drug substance or drug product is
z Chemical changes, which can be temperatures, can be used to determine the subjected: from manufacturing to final
observed in an increase in degradation shelf-life of the product or the re-test period application. Storage conditions are derived
products or decrease of assay (expiration time) for a drug substance. from real climatic conditions. Because most
chemical reactions follow logarithmic and not
z Microbial changes, like growth of Depending on the stage of stability, linear functions, this characteristic must be
microorganism, change in the efficiency product type and dosage form, the product take into consideration while defining
of preservative contents (e.g., is analyzed at intervals for various appropriate conditions. Rather than
antioxidant, antimicrobial preservative) parameters. These parameters may include calculating average temperatures, the mean
Last but not least, some changes are assays for the active ingredient, kinetic temperature (MKT), expressed by the
due to the container closure system where measurement of known degradation Arrhenius equitation, is used.
functionality tests (e.g. dose delivery system) products, dissolution time, appearance, etc.
Additionally, samples from production lots of The four major climate zones and the
must be executed during the stability study associated storage conditions stipulated in
in order to demonstrate full functionality of approved products are retained for stability
testing in case of product failures or current stability guidelines are summarized
the entire “product” during the shelf-life
in Table 1.
period.
Table 1 : Climatic Zones and Associated Storage Conditions
Stability studies are incorporated at all
Climatic Zone Calculated data Derived data
stages of the drug product life cycle - from
Countries Temp. MKT Humidity Temp. Humidity
early stages of product development to late
°C °C %R.H. °C %R.H.
stage follow-up stabilities. In particular the
life cycle can be segregated into 6 different Climatic Zone I
stages: “Temperate” 20 20 42 21 45
Japan, United Kingdom’ Northern
z Stage 1: Early stage stress- and Europe, Canada, Russia, United States Storage condition acc to ICH Q1A:25°C/60% R.H.
accelerated testing with drug Climatic Zone II
substances “Mediterranean, Subtropical” 21.6 22 52 25 60
z Stage 2: Stability on pre-formulation Japan, United States, Southern
batches Europe Storage condition acc to ICH Q1F 30°C/65% R.H.

z Stage 3: Stress testing on scale-up Climatic Zone III


batches “Hot, dry” 26.4 27.9 35 30 35
Iran, Iraq, Sudan
z Stage 4: Accelerated and long term
testing for registration purposes Climatic Zone IV
“Hot, humid” 26.7 27.4 76 30 70
z Stage 5: On-going Stability Testing Brazil, Ghana, Indonesia,
z Stage 6: Follow-up Stabilities Nicaragua, Philippines

E-mail : [email protected]

Pharma Times - Vol 42 - No. 07 - July 2010 13


Regulations and Table 2 : Guidelines Derived from ICH Q1A (R2)
Guidances Organization Guidelines

The ICH (International Conference on ASEAN Guideline “Stability Studies of Drug Products”
Harmonization of Technical Requirements of
Pharmaceuticals for Human Use) Guidelines US-FDA Guidance for Industry “Stability Testing of Drug Substances
Q1A(R2) “Stability testing of new drug and Drug Products; June 1998”
substances and products” is the “gold TRS 863, Annex 5: “Guidelines for stability testing of
standard” for conducting stability studies. WHO pharmacutical products containing well established drug
This is valid for “new drug substances or drug substances in conventional dosage forms”
products that are sufficient for a registration
Note for Guidance on Stability Testing of existing active
application within the three regions of the EC, EMEA substance and Related Finished products (Draft), February 2002
Japan, and the United States” - the intended
scope of the guideline. Moreover this
guideline (or previous version of it) forms the countries in Climatic Zone IV expressed their determined that the WHO stability guidelines
foundation for other guidelines published wish to include a larger safety margin for should be amended to reflect conditions for
world-wide (Table 2). medicinal products to be marketed in their Zone IV as follows:
region than previously foreseen in ICH Q1F
To address the fast growing market z Zone IVa: 30°C / 65% R.H.
(“Stability Data Package for Registration
segment, ICH Q5C “Quality of Biotechno- z Zone IVb: 30°C / 75% R.H
Applications in Climatic Zones III and IV”).
logical products – stability testing of As a consequence, several countries and The Committee further resolved that
Biotechnological/Biological products” must regions have revised their own stability each individual Member State within the
be emphasized as an important reference for testing guidelines, defining up to 30°C/75 % former Zone IV will need to classify itself as
stability of biopharmaceutical products. as the long-term storage conditions for hot Zone IVa or IVb. This process is still ongoing
Finally, discussions regarding stability and humid regions. Due to this divergence and leads into a situation where some of the
testing for registration in Climatic Zone III and in global stability testing requirements, the benefits of the former “harmonized” system
IV caused some confusion and uncertainties ICH Steering Committee has decided to may be lost.
in recent years. At a WHO meeting, entitled withdraw ICH Q1F and to leave the definition
of storage conditions in Climatic Zones III and There are additional facts that need to
“Stability Studies in a Global Environment”,
IV to the respective regions and the WHO. be taken into consideration when registering
held in Geneva, December 2004, it adopted
products in Zone III/IV countries. Testing
changes to stability testing requirements at In assessing the impact of the under more restrictive conditions might
an international level resulting in the following withdrawal of ICH Q1F on intermediate impact the packaging material used since it
stability long-term study conditions for hot testing conditions defined in ICH Q1A (R2), must be more protective. Also, early stage
and humid climates: a decision was made to retain 30°C/65%. stability studies become more important, as
z 30°C/65% R.H. e.g. WHO*, ICH*, However, regulatory authorities in the ICH manufacturers must clearly understand the
SADC*, GCC*, Brazil regions have agreed that the use of more robustness of their product in terms of
z 30°C/70% R.H. e.g. WHO previous, stringent humidity conditions such as 30°C/ sensitivity to moisture. Finally manufacturers
Cuba, Brazil previous 75% will be acceptable should the applicant must decide whether they are seeking a local
z 30°C/75% R.H. e.g. ASEAN* decide to use them. / single country application versus a global
approach. This decision will largely define the
These changes were based on new At the 40 th WHO Expert Committee
stability protocols. An example of a generic,
calculations and discussions where some Meeting (Oct. 2005), the Committee
global protocol is listed in Table 3 .

Table 3 : Example of a Generic, Global Protocol

Temp./Humidity Condition Climatic Zone Timepoint


t=0 t=1 t=3 t=6 t=9 t=12 t=18 t=24 t=36

25°C / 60% R.H. Long-term I and II x x x x x x x x

30°C / 65% R.H. Intermediate I and II (x) (x) (x) (x) (x) (x) (x) (x)
Long-term III and IV a

30°C / 75% R.H. Long-term IV b x x x x x x x x

40°C / 75% R.H. Accelerated I, II, III and IV (x) x x

50°C Stress - (x) x -

Conclusion To ensure that this happens, drug testing capabilities set-up for this specific
manufacturers need to thoroughly follow purpose and a built-in quality management
A successful stability study will establish regulations and guidelines and watch for system which suit international standards like
the shelf-life date of the drug product, the material study results. Taking particular care US-FDA and EU-GMP. Currently 14 Quality
retest period of a drug substance and in materials selection, tooling design and Control Labs are already established
appropriate storage conditions – but that’s integrity testing is critical to the success of worldwide.
not all. A successful stability study must also the product. For more information, please also visit
ensure that patients receive a safe and SGS’ Life Science Services offers you our Stability Studies web page or contact the
effective medicine. teams of experts with detailed knowledge, author.

14 Pharma Times - Vol 42 - No. 07 - July 2010

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