PA 2 LEC Module 2 (Midterm)

• quality systems - it has been recognized in the pharmaceutical industry
• quality risk management - is a valuable component of an effective quality system.
• risk - is defined as the combination of the probability of occurrence of harm and the severity of that harm.
• The manufacturing and use of a drug (medicinal) product, including its components, necessarily entail some degree of risk.
• product quality - is assured based on appropriate risk based decision-making throughout the product lifecycle
• Phase 1: 50-200 healthy subjects (usually) or patients who are not expected to benefit from the IMP. Studies pharmacokinetics and pharmacodynamics
• Phase 2: 100-400 patients with the target disease.
• Phase 3: 1000-5000 patients with the target disease.

  is the IMP really safe w/ patients?

  does the IMP really work in patients?
• Phase 4: Many thousands or millions of patients with the target disease:

  studies pharmacovigilance, compared w/ similar meds
• Quality risk management - is a systematic process for the assessment, control, communication and review of risks to the quality of the drug (medicinal) product across the product lifecycle.
• Initiate

  Quality Risk Management Process:

  Risk Assessment

  1. Hazard Identification (unacceptable…)
  2. Risk Analysis
  3. Risk Evaluation

  Risk Control (Risk Management)

  1. Risk Reduction (unacceptable)
  2. Risk Acceptance

  Output/ Result of the Quality Risk Management Process

  Risk Review

  1. Review events
• Two primary principles of quality risk management are:

  1. The evaluations of the risk to quality
  2. The level of effort, formality and documentation
• The evaluations of the risk to quality - it should be based on scientific knowledge and ultimately link to the protection of the patient.
• The level of effort, formality and documentation of the QRM process - it should be commensurate with the level of risk.
• The objective seeks to exemplify the core stability data package for new drug substances and products, but leaves sufficient flexibility to encompass the variety of different practical situations that may be encountered due to specific scientific considerations and characteristics of the materials being evaluated.
• General Principles

  The purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity, and light, and to establish a re-test period for the drug substance or a shelf life for the drug product and recommended storage conditions.
• climate - is different in all the countries in the world.
• Stability - this studies of the pharmaceutical drug should be done according to the climatic conditions of the country.
• According to the ICH guidelines for stability studies, the climate of the world is divided into five different zones. (ICH Stability Zones)

  1. zone l: temperature zone
  2. Zone ll: Mediterranea/Subtropical zone
  3. Zone lll: Hot dry zone
  4. Zone lVa: Hot humid/tropical zone
  5. Zone lVb: Hot/higher humidity
• Stress testing - using this method in testing 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 validate the stability indicating power of the analytical procedures used.
• stress testing - its nature will depend on the individual drug substance and the type of drug product involved.
• Stress testing - is likely to be carried out on a single batch of the drug substance.
• stress testing - should also evaluate the susceptibility of the drug substance to hydrolysis across a wide range of pH values when in solution or suspension.
• Photostability testing - should be an integral part of stress testing.
• Selection of batches: Data from formal stability studies should be provided on at least three primary batches of the drug substance. The batches should be manufactured to a minimum of pilot scale by the same synthetic route as, and using a method of manufacture and procedure that simulates the final process to be used for, production batches.
• Container Closure System

  The stability studies should be conducted on the drug substance packaged in a container closure system that is the same as or simulates the packaging proposed for storage and distribution.
• Stability studies - should include testing of those attributes of the drug substance that are susceptible to change during storage and are likely to influence quality, safety, and/or efficacy.
• The testing should cover, as appropriate, the physical, chemical, biological, and microbiological attributes. Validated stability-indicating analytical procedures should be applied. Whether and to what extent replication should be performed will depend on the results from validation studies.
• ICH stability - studies involve a drug substance tested under storage conditions and assess its thermal stability and sensitivity to moisture.

  The long-term testing should be performed over a minimum of 12 months at 25 ° C ± 2 °C/60% RH ± 5% RH or at 30 °C ± 2 °C/65% RH ± 5% RH
• drug substance - generally should be evaluated under storage conditions (with appropriate tolerances) that test its thermal stability and, if applicable, its sensitivity to moisture.
• The storage conditions and the lengths of studies chosen should be sufficient to cover storage, shipment, and subsequent use.
• The long term testing should cover a minimum of 12 months’ duration on at least three primary batches at the time of submission and should be continued for a period of time sufficient to cover the proposed re-test period.


  Tables below for further understanding: