Regulatory Requirement for Stability Study
Assessment of USFDA Warning Letters & 483’s Related to Improper Handling of OOS Results
October 27, 2020
Overview of Scale-Up and Post-Approval Changes (SUPAC)
November 21, 2020
Introduction:
Pharmaceutical products shelf-life estimation by assessing through systematic stability study is regulatory requirement, during this review current regulatory requirements elaborated.
The main aim of this study is to produce indication about how the drug substance and drug product quality is changes with time by exposed to different climate conditions like temperature, humidity and photolytic condition. Stability study helps to established retest period for the drug substance and validity of drug product and proposed storage conditions and proves that it meets it’s set specifications.
What is Stability?
Stability defines as, “The formulated products remains stable during it’s period within it’s physical, chemical, microbiological, pharmacological and medicinal specification in its designated packaging state”. Stability study is vital requirement to prove the safety and efficacy of pharmaceutical drug substances and drug products.
Factors Affecting Stability of Drug Substances and Drug Products:
Due to following physical or chemical variations forms in drug substances and drug products resulted into the degradation and subsequently reduction of assay or potency and formation of impurities.
- Oxidation/Reduction reaction
- Moisture content
- Temperature
- pH
- Hydrolysis
- Light
- Concentration of drug
- Particle size
- Package integrity
Different Stages and Kinds of Stability Studies:
Different Stages of Stability Studies: Following are the various stages of stability studies performed from the various stages of formulation development to the registration of drug substances or drug products. Each stage of formulation development ensures to satisfy the set specification up to the proposed period of it’s shelf life.
- Drug substance stability study,
- Formulation development study batches stability study,
- Scale up batch/Preclinical and Clinical study batches stability study,
- Exhibit batches or Registration batches stability study,
- Commercial or Marketed products stability study
Different Kinds of Stability Studies: Following are the various kinds of stability studies were performed which are mainly of 4 types:
- Long term stability study,
- Intermediate stability study,
- Accelerated stability study,
- In-use stability study.
Stability Study Protocol:
Stability study protocol is most significant document to stipulate the activities to be applied out during stability studies. Stability study protocol illustrate the following details:
- Specification
- Standard test procedure
- Batch details
- Packaging details
- Sampling time points
Different Zone for Stability Study Testing:
The world is divided into 4 different geographical zone on the basis of climate and pharmaceutical drug products probably exposed during their storage condition. The storage conditions obtained on the basis of average yearly temperature and relative humidity.
| Zone | Climate Type | Temperature/Humidity (Long Term Condition) | Temperature/Humidity (Accelerated Condition) |
| Zone I | Moderate Zone | 21° ± 2°C/45%RH ± 5%RH | 40° ± 2°C/75%RH ± 5%RH |
| Zone II | Mediterranean/Subtropical | 25° ± 2°C/60%RH ± 5%RH | 40° ± 2°C/75%RH ± 5%RH |
| Zone III | Hot Dry Zone | 30° ± 2°C/35%RH ± 5%RH | 40° ± 2°C/75%RH ± 5%RH |
| Zone IVa | Hot Humid/Tropical Zone | 30° ± 2°C/65%RH ± 5%RH | 40° ± 2°C/75%RH ± 5%RH |
| Zone IVb | Hot/Higher Humidity | 30° ± 2°C/75%RH ± 5%RH | 40° ± 2°C/75%RH ± 5%RH |
| Cool | Refrigerated | 5° ± 3°C/No Humidity | 25° ± 2°C/60%RH ± 5%RH |
| Coldest | Frozen | – 15° ± 5°C/No Humidity | 5° ± 3°C/ No Humidity |
Conclusion:
The main target of the study is to prove that the how the drug substance or drug product behaves during it’s storage of various temperature and humidity conditions. As per the regulatory requirement of stability, the results obtained of drug substance and drug products demonstrates that the identity, strength, efficacy and quality is unchanged during it’s storage condition as per the set specifications.
References:
- U.S.FDA, Title 21 of the U.S. code of Federal Regulations.21 CFR 211-Current Good Manufacturing for Finished Pharmaceuticals,
- ICH, Q1A (R2) Stability Testing in New Drugs and Products,
- ICH, Q1B Photo-Stability Testing of New Drug Substances and Products,
- ICH, Q1C Stability testing of New Dosage Forms,
- ICH, Q1D Bracketing and Matrixing Designs for Stability Testing of Drug Substances and Drug Products,
- ICH, Q1E Evaluation of Stability Data,
- ICH, Q1F Stability Data Package for Registration in Climatic Zones III and IV,
- ICH, Q5C Quality of Biotechnological Products: Stability testing of Biotechnological/Biological Products,
- R.G. Hill and H.P. Rang, Eds., Drug Discovery and Development: Technology in Transition (Churchill Livingston, Elsevier, Edinburgh, Scotland, 2nd Ed., 2012),
- K. Huynh-Ba, Ed., Handbook of Stability Testing of Pharmaceutical Products: Regulations, Methodologies and Best Practices (Springer, New York, 2009),
- K. Waterman, Understanding and Predicting Pharmaceutical product Shelf life, In Handbook of Stability Testing of Pharmaceutical Products: Regulations, Methodologies and Best Practices (Springer, New York, 2009),
- WHO Expert Committee on Specifications for Pharmaceutical Preparations Fifty-second report, annex 10, Stability testing of active pharmaceutical ingredients and finished pharmaceutical products (World Health Organization, 2018).
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