Forced Degradation or Stress Testing

1.0 OBJECTIVE

To lay down the procedure for Forced Degradation or Stress Testing.

2.0 SCOPE

This SOP is Applicable for Forced Degradation or Stress Testing in Company Name

3.0  BACKGROUND

Not Applicable

4.0 RESPONSIBILITY

4.1 AR & D -Chemist 

4.2 Group Leader Analytical research to ensure proper and safe operation of the Equipment.

4.3 Head - Analytical research or his designee to ensure overall compliance.

5.0 PROCEDURE

5.1 Stress testing of the drug substance can help identify the likely degradation products, which can in turn help establish the degradation pathways and the intrinsic stability of the molecule and/or validate the stability indicating power of the analytical procedures used. 
5.2 The nature of the stress testing will depend on the individual drug substance involved.
5.3 Stress testing is likely to be carried out on a single batch of the drug substance. The forced degradation testing should not be part of formal stability program.
5.4 The temperature/ humidity conditions used may be more severe than the typical accelerated stability testing conditions inorder to generate potential degradation products.

5.5 How much degradation is Required? 
While performing the forced degradation studies question may arise, how much is degradation is enough in stress testing. To answer this question, we classified the forced degradation into the following types.  

1. Deceptive:  Degradation level is good(<15%)  but no relevant degradants are observed 
2. Predictive:   Degradation level is good(<15%)  but one or more relevant degradants are observed.
3. Useless:  Between 15 to 100% degradation but no  relevant degradants are observed.

From the above three scenarios, predictive scenarios is the ideal one to perform.
Requirement for Predictive degradation: 
* Should lead to the degradation of main compound, but not more than 5-15% 
* Should lead to the good predictability of degradation pathways( i.e a low probability of drastic or false degradation)

5.6 Parameters in Forced degradation:
The typical forced degradation studies on drug substance include
  1. Temperature and or with humidity
  2. Acid/base Stress testing 
  3. Oxidation(H2O2)
  4. Photodegradation
  5. pH variation(high and low)

 Study
 Challenge Conditions
 Time Points 
 Acidic/Solution
 HCl (1.0N, RT, 70°C)
 Initial –7 days
 Basic/Solution
 NaOH (1.0N, RT, 70°C)
 Initial –7 days
 Oxidative/Solution
 H2O2+ Initiator
 7 Days
 Thermal
 70°C/30% RH
 6 weeks
 Thermal/Humidity
 70°C/75% RH
 6 weeks
 Photo (UV light)*
 1,000 watt hrs/m2, RT
 5 X ICH
 Photo (Fluorescent light)*
 6 x 106 lux hrs, R.T.
 5 X ICH
 * RT is room temperature
5.6.1 Oxidation:
Hydrogen peroxide is the most commonly used for oxidation of drug substances in forced degradation studies. The peroxide concentrations may be adjusted as necessary to obtain 5-20% degradation. Usually diluted hydrogen peroxide of 0.3 to 3% can be used, but peroxide radicals are very reactive but non selective and relatively unpredictable in results. Stress with Hydrogen peroxide often leads to secondary degradation products of the primary degradation products making the results interpretation more difficult.
Peroxide radicals react with low energy C-H bonds or C=C bonds, so amines, sulfides and carbon carbon double bonds are susceptible to peroxide radicals and give corresponding N-oxides, sulfoxides and epoxides respectively.
Radical initiators such as AIBN(2,2-Azobisisobutyronitrile), ACVA(azobis cyan Valeric acid) and AMPD(Azobis methyl propionamide dihydrochloride) are better choices but are less commonly used. These are generally more selective than peroxides and can be used to confirm/invalidate the peroxide results.
An appropriate temperature for reaction is 40°C. The test may be stopped after 5-20% degradation or after 7 days if no degradation was observed.
5.6.2 Acid/Base Stress testing:
Acid/Base stress testing is performed to force the degradation of a drug substance to its primary degradation products by exposure to acidic or basic conditions over time. The functional groups likely to introduce acid/base hydrolysis are compounds that have labile carbonyl functionality such as amides(lactams), esters(lactones), carbamates, imides, imines, alcohols and aryl amines.  
Solubilities of atleast 1mg/ml of 1N HCl(acidic) or IN NaOH(Basic) conditions are recommended for acid / base stress testing. If the compounds are poorly water-soluble in HCl/NaOH, then co-solvents may be used in combination with acid or base. Special attention should be taken to drug substance structure while selecting the co-solvent. Following is the list of solvents for specific conditions.

  • DMSO, acetic acid, propionic acid are useful for acidic conditions

  • DMSO, N-methylpyrrolidone(NMP) and acetonitirle(ACN) work under neutral condition

  • Glyme and 1,4-dioxane facilities reactions in base

  • ACN is choice for photochemical reaction

  • Avoid methanol for –Co2H, amide, -OH, ArNH2

  • Stress testing is typically initiated at room temperature. If no degradation occurs, an elevated temperature is applied (50-70°C). Maximum stress time should not be exceeding 7 days. The degraded sample often neutralized using acid/base/buffer to avoid further decomposition.
    5.6.3 Thermal / Thermal/ humidity stress testing:
    Thermal or thermal/humidity stress testing is performed to force the degradation of a drug substance to its primary degradation products by exposure to Thermal or thermal/humidity conditions over time.
    To evaluate stability utilizing elevated temperatures stress conditions are selected on a conservative estimate of Arrhenius expression. Based on this estimate, a 10°C in temperature results in doubling in reaction rate and decrease in reaction time by a factor of 2. Using this rule 70°C for 6 weeks study is recommend to predict 2 years room temperature shelf life. For thermally unstable compounds 60°C for 6 weeks of study may be recommended.
    The stress testing conditions for  thermal/humidity are 70°C/30%RH and  70°C/75%RH. These starting conditions are modified if a compound undergoes a change in physical form at or below this elevated temperature. 
    For low temperature storage drug substances( 5°C), 40°C is the reasonable temperature for stress studies.

    6.0 ANNEXURES
    NIL

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