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Stability studies


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stability studies on drug Substances

stability studies on drug Substances

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  • 1. On Drug Substances Author: Srikanth N http://stabilitystudies.blogspot.com4/30/2012 1
  • 2. Terminology  Re-test date  The date after which samples of the drug substance should be examined to ensure that the material is still in compliance with the specification and thus suitable for use in the manufacture of a given drug product.  Re-test period  The period of time during which the drug substance is expected to remain within its specification and, therefore, can be used in the manufacture of a given drug product, provided that the drug substance has been stored under the defined conditions.  Primary batch  A batch of a drug substance used in a formal stability study, from which stability data are submitted in a registration application for the purpose of establishing a re-test period .A primary batch of a drug substance should be at least a pilot scale batch.4/30/2012 2
  • 3. Terminology  Mass balance  The process of adding together the assay value and levels of degradation products to see how closely these add up to 100% of the initial value, with due consideration of the margin of analytical error.4/30/2012 3
  • 4. Objective  Stability studies are conducted to assesses the effect of Tempeature, Humidity and Light and to assign the retest period and to recommend the storage conditions.4/30/2012 4
  • 5. Types  Three types of Stability Studies  Accelerated  Studies designed to know the shortterm Excursions of temperature on the drug Substances  Intermediate  Studies conducted, incase of failure in accelerated studies and the conditions of temperature and humidity are in between long term and accelerated.  Long term  Studies designed to check the stability of the drug substnace.4/30/2012 5
  • 6. Stability Protocol  Batch selection  Container Closure System  Specifications  Testing frequency  Storage conditions  Sample Quanity  Statements and labelling  Stability commitment4/30/2012 6
  • 7. Batch Selection  Three Primary batches of drug susbtance are to be kept for stability studies  Usually three commercial batches to be kept in studies and the batches may be first three batches.  One add-on batch for every year. This might be the first batch of that year4/30/2012 7
  • 8. Container Closure System  Stability Studies to be conducted in the container closures that are similar to the containers in which the Drug susbtance is marketting.  For example, Itraconazole is stored in trasparent polyethylene bag[primary packing] and which inturn stored in black polyehtylene bag and finally in HDPE container[secondary packing].4/30/2012 8
  • 9. Specification  Stability analysis is perfomed for the test parameters which are prone to change during the storage and are likely to influence the Qality, safety and Efficacy.4/30/2012 9
  • 10. Testing Frequency  Testing frequency for accelerated and long term as follows  Accelerated: 0,1,2,3 and 6 Months  Long term: 0,3,6,9,12,18,24,36,48 and 60 Months4/30/2012 10
  • 11. Storage Conditions Type of study Accelerated Long term Intermediate General 40°C±2°C, 25°C±2°C, 30°C±2°C, Case 70±5% RH 60±5% RH 65±5% RH Refrigeraed 25°C±2°C, 5°C±3°C -- 60±5% RH Freezer -20°C±5°C -- --4/30/2012 11
  • 12. Sample Quantity  Sample Quantity is determined on the analytical parameters under study Specification Accepatance Quantity[G] Crieteria Description White to almost white 1 g [reusable] power Identification by IR Sample spectrum 300 mg should be concorddant with that of the sample spectrum Loss on drying NMT 0.05% 1g4/30/2012 12
  • 13. Sample Quantity Specification Acceptance Crieteria Quantity{G} Related Substances Monaamide impurity –NMT 0.15% 1g Dimer Impurity-NMT 0.15% Unknown impurity-NMT 0.10% Total Impurity-NMT 1,0% Assay by HPLC Between 98.0-102.0 % 1g Total 3.3 g(rounded to 4 g)4/30/2012 13
  • 14. Sample Quantity  For accelerated Studies  Time points: 0,1,2,3 and 6 Months [Total 4 time point excluding intial]  For each time point: 4 g  Total: 4 x 4 g = 16 g  For Long term Studies  Time points: 0,3,6,9,12,18,24,36,48 and 60 Months [Total 9 time point excluding intial]  For each time point: 4 g  Total: 9 x 4 g = 36 g4/30/2012 14
  • 15. Sample Quantity  Accelerated : 16 g+ 5 g extra= 21 g  Long term: 36 g + 10g =46 g  Total = 67 g [rounded to 70 grams]4/30/2012 15
  • 16. Storage Statements and Labelling Statement condition Label statement 25ºC / 60% RH (Long term) Do not store above 25°C 40ºC / 75% RH (Accelerated term) 25ºC / 60% RH (Long term) Do not store above 25°C 30ºC / 65% RH (Intermediate, failure at long term) 30ºC / 65% RH (Long term) Do not store above 30ºC 40ºC / 75% RH (Accelerated term) 5ºC +/- 3ºC Store in a refrigerator (2 to 8ºC) -20ºC +/-5ºC Store in freezer4/30/2012 16
  • 17. Stability Commitment  It is commitment given to the reulatory authorities or customers.  All three batches of stability from production, studies to be conducted through the assigned retest period.  Less than 3 batches, commitment to add the immediate prodcution batches to make 3 batches and continue through the retest period assigned.  No match from production, first three production batches to be kept for stability studies continue through the retest period assigned.4/30/2012 17
  • 18. Stress Testing  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.  Stress testing to be carried out on a single batch of the drug substance.  Parameters in stress testing  Acid Hydrolysis[0.1N HCl]  Base Hydrolysis[0.1N NaoH]  Oxidation[3% H2O2]  Temperature with Humidity  Photodegradation4/30/2012 18
  • 19. Conditions Study Chanllenge conditions Time Points Acid/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 6 x 106 lux hrs, R.T. 5 X ICH light)*4/30/2012 19
  • 20. Others  Stability Evaluation  Data Variability and many more refer to  http://stabilitystudies.blogspot.com4/30/2012 20