Stress Testing Study Design

Drug-Degradation-Mechanism
Drug Degradation Mechanism
July 17, 2020
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Polymorphic Impurities: Risk Assessment & Investigation
July 21, 2020
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Introduction

There is no particular guideline available for How to perform the stress study. There are some guidelines of the International Conference on Harmonization (ICH) on the stability testing of drug substances and drug products, for stress testing but is indefinite and not very much useful for the execution of stress study. Stress study is to be carried out on a representative batch of the drug substance.

Initial Stress Study Conditions:

Thermal stress condition:

Thermal stress study condition can be performed above the accelerated stability testing condition i.e. If its 40°C then it is in the proportion of 10°C increments, e.g., 50°C, 60°C (75% RH), 70°C, etc. always from lower to higher temperature condition. Exposer time (1 Hr., 2 Hrs, 5 Hrs, 10 Hrs, 16 Hrs, 1 Day, 2 Days, etc.) need to be optimized depending on the sufficient degradation i.e. minimum 5 % degradation. Ideally need optimum degradation 5 % to 10 % with optimum time. If more than 10 % degradation i.e. excessive degradation happened at more extreme stress conditions it often provides data that are confounded with secondary or tertiary degradation products. Degradation triggered by exposure to temperatures includes bond breakage i.e. pyrolysis. Any degradation mechanism that is enhanced at elevated temperatures is thermolytic pathways include Hydrolysis, Dehydration, Isomerization, Decarboxylation, Rearrangement, Polymerization reactions, pyrolysis. In general, the rate of reaction increases with an increase in temperature. Many drug substances are sensitive to heat or topical temperatures such as vitamins and peptides. Hence need to optimize the temperature and exposer time carefully.  

The stress study should also assess the exposure of the drug substance to hydrolysis over the wide range of pH values (pH 1, 2, 4, 6, 8, 10, 12, 14 etc.) in solution or suspension state.

Acidic stress conditions:

Acid stress study conditions can be performed from the minimum acidic concentration i.e. 0.01 N HCl or any other suitable acid e.g. Sulfuric acid, Nitric acid, Acetic acid, etc. The degraded sample is then neutralized using a suitable base or buffer, to stop further decomposition.

Following are the possible acidic conditions with exposer time.

ConcentrationTemperatureTime
0.01 N, 0.1 N, 1 N to 5 NRoom Temperature, 40°C, 50°C, 60°C, 70°C etc.1 Hr., 6 Hrs., 12 Hrs., 1 day, 2 Days and up to 5 Days.

Basic stress conditions:

Base stress study conditions can be performed from the minimum basic concentration i.e. 0.01 N NaOH or any other suitable base e.g. Potassium Hydroxide, Lithium hydroxide, Diisopropylamine, etc. Optimize the degradation of 5 % to 10 % with the optimum time. The degraded sample is then neutralized using suitable acid or buffer, to stop further decomposition. The following are the possible basic conditions with exposure time.

ConcentrationTemperatureTime
0.01 N, 0.1 N, 1 N to 5 NRoom Temperature, 40°C, 50°C, 60°C, 70°C etc.1 Hr., 6 Hrs., 12 Hrs., 1 day, 2 Days and up to 5 Days.

Neutral condition:

Neutral stress study conditions can be performed by using purified water. The following are the possible basic conditions with exposure time.

TemperatureTime
Room Temperature, 40°C, 50°C, 60°C, 70°C etc.1 Hr., 6 Hrs., 12 Hrs., 1 day, 2 Days and up to 5 Days.

Oxidative stress conditions:

Normally, hydrogen peroxide is used for oxidative conditions. Apart from this as metal ions, oxygen, and radical initiators: 2,2-azobisisobutyronitrile (AIBN, Vazo 64 ) or 2,2- azobis-(2,3-dimethylvaleronitrile) (Vazo 52) can also be used. Drug structure will allow selecting the concentration and condition of oxidizing agents. An electron transfer mechanism occurs in the oxidative degradation of drug substances. 0.1%-5% hydrogen peroxide at neutral pH, samples can be analyzed at different time intervals to determine the desired level of degradation.

ConcentrationTemperatureTime
0.1 %, 1 %, 3 %, 5 % etcRoom Temperature and 40°CImmediate to 1 Hr., 6 Hrs., 12 Hrs., 1 day, 2 Days, and up to 5 Days.

Photostability

Photostability testing should be an important part of stress testing, especially for photo-labile compounds. Some recommended conditions for photostability testing are described in ICH Q1B Photostability Testing of New Drug Substances and Products. Samples of drug substance, and solid/liquid drug product, should be exposed to a minimum of 1.2 million lux hours and 200-watt hours per square meter light. The same samples should be exposed to both white and UV light. To minimize the effect of temperature changes during exposure, temperature control may be necessary. Maximum 6 million lux/Hrs is the recommended radiations.

Conclusion:

The initial stage stress test results for drug substances can be relatively helpful for formulators of the drug product as well as to those responsible for developing the analytical methods for the drug product. If no degradation can be induced at these proposed maximum stress conditions, then it is concluded that the molecule is stable and can be justified accordingly. Stress testing provides valuable insight into the selection of physical form, stereochemical stability, packaging, and storage conditions of a drug substance.

References:

  1. FDA, “Guidance for Industry Q1A (R2): Stability Testing of New Drug Substances and Products.
  2. FDA, “Guidance for Industry ICH Q2A: Text on Validation of Analytical Procedures,”
  3. FDA, “Guidance for Industry ICH Q2B: Validation of Analytical Procedures: Methodology,”.
  4. FDA, “Guidance for Industry: Analytical Procedures and Methods Validation: Chemistry, Manufacturing and Controls Documentation,”
  5. Pharmaceutical Stress Testing, Predicting Drug Degradation, Second Edition, Edited by, Steven W. Baertschi, Eli Lilly and Company, Indianapolis, Indiana, USA, Karen M. Alsante, Robert A. Reed.
  6. S.W. Baertschi, “Chapter 15: Forced Degradation and Its Relation to Real Time Drug Product Stability,” in Pharmaceutical Stability Testing to Support Global Markets.
  7. K.M. Alsante, et al., “Chapter 3: Degradation and impurity analysis for pharmaceutical drug candidates” in Handbook of Modern Pharmaceutical Analysis.

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