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

Any physical, chemical or micro-biological change in the product potentiallyimpact the efficiency and integrity of the finalproduct and may therefore directly orindirectly impact patients’ health. There arethree major types of “changes”:

Physical changes, which might effectthe appearance, melting point, clarityand color of solution, water, crystalmodification (polymorphism) or particlesize

Chemical changes, which can beobserved in an increase in degradationproducts or decrease of assay

Microbial changes, like growth ofmicroorganism, change in the efficiencyof preservative contents (e.g.,antioxidant, antimicrobial preservative)

Last but not least, some changes aredue to the container closure system wherefunctionality tests (e.g. dose delivery system)must be executed during the stability studyin order to demonstrate full functionality ofthe entire “product” during the shelf-lifeperiod.

Stability studies are incorporated at allstages of the drug product life cycle - fromearly stages of product development to latestage follow-up stabilities. In particular thelife cycle can be segregated into 6 differentstages:

Stage 1: Early stage stress- andaccelerated testing with drugsubstancesStage 2: Stability on pre-formulationbatchesStage 3: Stress testing on scale-upbatchesStage 4: Accelerated and long termtesting for registration purposes

Stage 5: On-going Stability TestingStage 6: Follow-up Stabilities

In early stages, stability studies areconducted on the API to gather informationabout physical and chemical properties(solubility profile, hydroscopicity, thermal -and chemical stability) and to determine apreliminary re-test period and storageconditions. Accelerated stability testing canbe used as a “worst case” evaluation touncover the kinds of degradation productspotentially found after long-term storage.Gentle conditions (recommended for long-term storage) and slightly elevatedtemperatures, can be used to determine theshelf-life of the product or the re-test period(expiration time) for a drug substance.

Depending on the stage of stability,product type and dosage form, the productis analyzed at intervals for variousparameters. These parameters may includeassays for the active ingredient,measurement of known degradationproducts, dissolution time, appearance, etc.Additionally, samples from production lots ofapproved products are retained for stabilitytesting in case of product failures or

production process changes. Retainedsamples can be tested alongside returnedsamples to determine whether the root causeof the problem was manufacturing or storagerelated.

Climatic ZonesA very important point in conducting

stability studies are the storage conditions.They should simulate the conditions underwhich the drug substance or drug product issubjected: from manufacturing to finalapplication. Storage conditions are derivedfrom real climatic conditions. Because mostchemical reactions follow logarithmic and notlinear functions, this characteristic must betake into consideration while definingappropriate conditions. Rather thancalculating average temperatures, the meankinetic temperature (MKT), expressed by theArrhenius equitation, is used.

The four major climate zones and theassociated storage conditions stipulated incurrent stability guidelines are summarizedin Table 1.

Conducting Stability Studies – Recent Changes toClimatic Zone IVUlrich Markens*Regional Head Asia-Pacific, SGS Life Science Services

E-mail : ulrich.markens@sgs.com

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

Table 1 : Climatic Zones and Associated Storage ConditionsClimatic Zone Calculated data Derived dataCountries Temp. MKT Humidity Temp. Humidity

°C °C %R.H. °C %R.H.

Climatic Zone I“Temperate” 20 20 42 21 45

Japan, United Kingdom’ NorthernEurope, Canada, Russia, United States Storage condition acc to ICH Q1A:25°C/60% R.H.

Climatic Zone II“Mediterranean, Subtropical” 21.6 22 52 25 60

Japan, United States, SouthernEurope Storage condition acc to ICH Q1F 30°C/65% R.H.

Climatic Zone III“Hot, dry” 26.4 27.9 35 30 35

Iran, Iraq, Sudan

Climatic Zone IV“Hot, humid” 26.7 27.4 76 30 70

Brazil, Ghana, Indonesia,Nicaragua, Philippines

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Pharma Times - Vol 42 - No. 07 - July 201014

Regulations andGuidances

The ICH (International Conference onHarmonization of Technical Requirements ofPharmaceuticals for Human Use) GuidelinesQ1A(R2) “Stability testing of new drugsubstances and products” is the “goldstandard” for conducting stability studies.This is valid for “new drug substances or drugproducts that are sufficient for a registrationapplication within the three regions of the EC,Japan, and the United States” - the intendedscope of the guideline. Moreover thisguideline (or previous version of it) forms thefoundation for other guidelines publishedworld-wide (Table 2).

To address the fast growing marketsegment, ICH Q5C “Quality of Biotechno-logical products – stabil ity testing ofBiotechnological/Biological products” mustbe emphasized as an important reference forstability of biopharmaceutical products.

Finally, discussions regarding stabilitytesting for registration in Climatic Zone III andIV caused some confusion and uncertaintiesin recent years. At a WHO meeting, entitled“Stability Studies in a Global Environment”,held in Geneva, December 2004, it adoptedchanges to stability testing requirements atan international level resulting in the followingstability long-term study conditions for hotand humid climates:

30°C/65% R.H. e.g. WHO*, ICH*,SADC*, GCC*, Brazil30°C/70% R.H. e.g. WHO previous,Cuba, Brazil previous30°C/75% R.H. e.g. ASEAN*

These changes were based on newcalculations and discussions where some

countries in Climatic Zone IV expressed theirwish to include a larger safety margin formedicinal products to be marketed in theirregion than previously foreseen in ICH Q1F(“Stability Data Package for RegistrationApplications in Climatic Zones III and IV”).As a consequence, several countries andregions have revised their own stabilitytesting guidelines, defining up to 30°C/75 %as the long-term storage conditions for hotand humid regions. Due to this divergencein global stability testing requirements, theICH Steering Committee has decided towithdraw ICH Q1F and to leave the definitionof storage conditions in Climatic Zones III andIV to the respective regions and the WHO.

In assessing the impact of thewithdrawal of ICH Q1F on intermediatetesting conditions defined in ICH Q1A (R2),a decision was made to retain 30°C/65%.However, regulatory authorities in the ICHregions have agreed that the use of morestringent humidity conditions such as 30°C/75% will be acceptable should the applicantdecide to use them.

At the 40th WHO Expert CommitteeMeeting (Oct. 2005), the Committee

determined that the WHO stability guidelinesshould be amended to reflect conditions forZone IV as follows:

Zone IVa: 30°C / 65% R.H.Zone IVb: 30°C / 75% R.H

The Committee further resolved thateach individual Member State within theformer Zone IV will need to classify itself asZone IVa or IVb. This process is still ongoingand leads into a situation where some of thebenefits of the former “harmonized” systemmay be lost.

There are additional facts that need tobe taken into consideration when registeringproducts in Zone III/IV countries. Testingunder more restrictive conditions mightimpact the packaging material used since itmust be more protective. Also, early stagestability studies become more important, asmanufacturers must clearly understand therobustness of their product in terms ofsensitivity to moisture. Finally manufacturersmust decide whether they are seeking a local/ single country application versus a globalapproach. This decision will largely define thestability protocols. An example of a generic,global protocol is listed in Table 3 .

Table 2 : Guidelines Derived from ICH Q1A (R2)

Organization Guidelines

ASEAN Guideline “Stability Studies of Drug Products”

US-FDA Guidance for Industry “Stability Testing of Drug Substancesand Drug Products; June 1998”

TRS 863, Annex 5: “Guidelines for stability testing ofWHO pharmacutical products containing well established drug

substances in conventional dosage forms”

Note for Guidance on Stability Testing of existing activeEMEA substance and Related Finished products (Draft), February 2002

ConclusionA successful stability study will establish

the shelf-life date of the drug product, theretest period of a drug substance andappropriate storage conditions – but that’snot all. A successful stability study must alsoensure that patients receive a safe andeffective medicine.

To ensure that this happens, drugmanufacturers need to thoroughly followregulations and guidelines and watch formaterial study results. Taking particular carein materials selection, tooling design andintegrity testing is critical to the success ofthe product.

SGS’ Life Science Services offers youteams of experts with detailed knowledge,

testing capabilities set-up for this specificpurpose and a built-in quality managementsystem which suit international standards likeUS-FDA and EU-GMP. Currently 14 QualityControl Labs are already establishedworldwide.

For more information, please also visitour Stability Studies web page or contact theauthor.

Table 3 : Example of a Generic, Global Protocol

Temp./Humidity Condition Climatic Zone Timepointt=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 -