Planning Stability Studies During Product Development, Subcontracting

Bob Seevers, Ph.D.

The Role of Stability in Drug Development

Stability studies play a central role in drug development Permit understanding of the molecule Essential for developing analytical methods Essential for selecting packaging for drug substance and drug product Essential for choosing storage conditions for drug substance and drug product

The Role of Stress Testing

Identification of degradation pathways Identification of degradants Determination of which type(s) of stress affect the molecule
Photostability High Temperature Low Temperature Oxidation pH extremes

Photostability
Light can affect drugs, causing chemical changes ICH Q1B guidance spells out how to do photostability tests Light sources
Combination of visible and UV light

Procedure
Samples should be exposed to light providing an overall illumination of not less than 1.2 million lux hours and an integrated near ultraviolet energy of not less than 200 watt hours/square meter Standards given identical exposure, but protected by light barrier such as aluminum foil

Temperature Extremes
Studies are typically done in increasing 10C increments (40C, 50C, 60C, etc.) until significant degradation is observed Freeze/Thaw studies
Particularly important for proteins and other biomolecules Example: insulin forms aggregates on freezing

Oxidation
Typically done by placing the drug substance in aqueous solution with hydrogen peroxide Goal is significant degradation
Can identify degradants Determine whether protective packaging is required Determine if an antioxidant should be considered for the drug product formulation

pH Extremes
Typically done by adding drug substance to buffered aqueous solutions at pH values from 1-10. Can be complicated by limited solubility of the drug substance under different pH conditions Again, the goal is significant degradation
Determine degradants Decide if the molecule will survive passage through the stomach
Is enteric coating necessary? Should the drug be given by injection?

Degradation Reactions
Oxidation
Thiols (R-SH) form disulfides (R-SS-R) Alcohols (RCH2-OH) form aldehydes (RHC=O) and acids (RC02H) Amines (R3N) can form amine oxides (R3N+O-)

Hydrolysis
Usually caused by high or low pH Esters (RCO2R ) form acids and alcohols (RC02H + R OH) Amides (RCONHR ) form acids and amines (RC02H + R NH2)

Accelerated Stability
Stability study run under more stressful conditions than expected for long term storage Different from stress studies in that the goal is to get a quick understanding of what may be expected from a Accelerated Conditions long term study Long-term conditions
Room temperature (2530C) Refrigerated (5 3C) Freezer (-20C 5C) 40C/75%RH 25C/60%RH 5 3C

Developing Analytical Methods

Results of stress studies provide degradants These need to be identified and quantitated Selection of method
Typically High Performance Liquid Chromatography (HPLC) Several types of solid phases available

But it is essential to have some method available to evaluate the results of stress studies Thus, stability studies and analytical method development work together
Start with drug substance molecule and separately synthesized possible degradants to determine method effectiveness

Methods Must be StabilityIndicating

Analytical methods must effectively separate and permit quantification of degradants Any significant changes in drug substance or drug product quality over time must be detectable
Increase in degradants Change in dissolution behavior Change in stereochemistry
cis to trans or vice-versa optical isomers interconverting

How much stability data is needed?

Pre-clinical
Toxicology studies Analytical method development Stability of the drug substance in the form used for testing must be demonstrated for the time frame of the studies
for tox studies this is typically a solution or suspension that may be used for a period of days or weeks for analytical development this is usually a solution in the solvent used to elute the column selected; such a solution may be used for an extended period of time, if stable or made fresh daily, if necessary

How much stability data is needed?

Phase I
Initial human studies Goal is to understand how well the drug is absorbed in vivo and determine whether it is reaching the selected target Studies may begin with only a small amount of stability data for the drug substance and limited or no stability data for the drug product If the drug substance is not stable, then more data are needed as well as drug product data

 Phase II

How much stability data is needed?

Goal is to determine dosing and get a limited sense of the effectiveness of the drug By this point in drug development there is usually more stability data available for the drug substance New routes of synthesis of the drug substance can lead to different patterns of change on stability due to the presence of different impurities, especially metals Stability data for the drug product in a formulation that should be the same or close to the intended commercial formulation is obtained Stability is obtained concurrently with clinical studies Failures on stability must be investigated promptly and appropriate action taken, possibly including recalling the drug from clinical sites.

How much stability data is needed?

Phase III
Large clinical studies to demonstrate the drugs safety and effectiveness Registration stability is typically done during this time
Final route of synthesis for drug substance Final formulation for drug product Final packaging for drug substance and drug product

How much stability data is needed?

At the time of Marketing Application Submission
ICH Q1A and WHO guidance recommend a minimum of 12 months long-term stability and 6 months accelerated This is a requirement in Europe This is negotiable in the US Expectations in other countries are similar

Drug Product Stress Studies

Extreme temperatures
determines whether excipients in the drug product formulation will react with the drug substance key to dealing with temperature excursions experienced by the drug product during distribution

Freeze/thaw
important if the drug product is at risk for experiencing temperatures <0C

Shock and Vibration

all products will undergo some amount of shock and vibration in the distribution process; how will this affect their quality

Determining Shelf-Life for Clinical Trials

Phase I
Shelf-life is typically extrapolated based on limited stability data for the drug substance In cases where the drug substance shows significant change, then drug product stability is required before human studies begin

Determining Shelf-Life for Clinical Trials

Phase II and Phase III
Shelf-life is based on stability from previous work and ongoing studies on current formulation Longer shelf-lives are generally needed due to more extensive clinical studies Stability studies are done concurrently with clinical studies Shelf-life can be extended as more stability data is obtained

Registration Stability Studies

Information from ICH Q1A and WHO guidances
Long-term conditions Room temperature (2530C) Refrigerated (5 3C) Freezer (-20C 5C) Stability Conditions 25C/60%RH or 30C/65%RH or 75%RH 5 3C -20C 5C

Intermediate conditions: 30C/75%RH if 25C used for long-term and significant change occurs

Selection of Long Term Stability Conditions

ICH Q1F attempted to define a single long term condition for all countries in climatic zone IV (hot and humid) of 30C/65%RH This was not acceptable to all countries and Q1F was withdrawn WHO has asked countries to choose between 30C/65%RH and 30C/75%RH WHO 2009 guidance lists 200 countries and their choice or WHOs best estimate

Selection of Long Term Stability Conditions

Practical implications of the complex Zone IV situation Most drug companies do their first registration in the US and Europe: Zone II countries with 25C/60%RH stability data Since generation of both 30C/65%RH and 30C/75%RH stability data is a double expense a choice must be made Since all Zone IV countries will accept 30C/65%RH data, this has become the default

Stability of Comparators
Comparators are used in clinical trials to test the new drug against standard therapy For a blinded trial, the comparator must be disguised, typically by overencapsulation The blinded comparator must be studied on stability Dissolution Degradation If compendial methods are not available, tests must be developed Shelf-life for comparator cannot exceed manufacturers expiration date

Stability of Placebos
Placebos must be evaluated on stability Appearance is the only attribute that needs to be tested If the appearance changes over time, the blinding of a study may be broken Placebos can be given a long shelf-life based on available data; if the color doesnt change over 12 months, it is not likely to change over 36 months

Subcontracting Stability Studies

This is often done to firms that can provide services
Stress Testing Analytical development Stability chamber storage Stability testing

It is essential to ensure that data from the contract lab is reliable

Auditing Stability Labs

Check their Quality Systems
Organization and Personnel Laboratory Controls Production and Process Controls Buildings and Facilities Material Handling Records, Reports, and Documentation

Create a Quality Agreement that clearly spells out expectations on both sides

Summary
Stability studies play a central role in drug development
Permit understanding of the molecule Essential for developing analytical methods, selecting packaging and storage conditions for drug substance and drug product

Stability data submitted to Health Authorities to support registration must be reliable