Ms. Caro

• Stability

  The ability of a particular formulation in a specific container or closure system to remain within its physical, chemical, microbiological, therapeutic and toxicological specifications
• Shelf life

  The duration of time during which a drug preparation will remain physically, chemically, therapeutically, toxicology and microbiology stable (possessing NLT 90% of the labeled potency)
• The period of stability of a preparation is the time from the date of manufacture of the formulation until its chemical or biological act. and is NLT 90% of the labeled potency
• The extent to which a product retains within specified limits and throughout its period of storage and use the same properties and characteristics that is possessed at the time of its manufacture
• Expiration Date

  The date placed on the container label of a pharmaceutical product designating the time prior to which a batch of the product is expected to remain within the approved shelf-life specification if stored under defined conditions, and after which it must not be used
• Stability Testing Studies

  Conducted to show long a pharmaceutical product can be stored at normal or accelerated conditions without any degradation to its properties
• Factors Affecting Stability of a Pharmaceutical Product

  • Stability of Active Ingredients
  • Potential Interactions between active and inactive ingredients
  • Manufacturing process
  • Container closure system
  • Environmental conditions
  • Storage
  • Handling
  • Length of time between handling manufacturing
• Product Stability Evaluations

  • Physical Stability
  • Chemical Stability
• Physical Stability

  Importance to formulators for appearance, uniformity, and availability of the active ingredient
• Chemical Stability

  Causes chemical deterioration incompatibilities which may be physical, chemical, or therapeutic
• Chemical causes of drug deterioration

  • Hydrolysis
  • Oxidation, Reduction
  • Racemization
  • Decarboxylation
  • Deterioration of H2O2 and Hypochlorites
  • Formation of precipitates
• Important Parameters

  • Drug Products: loss of activity or potency of the Active Ingredient, amount of degradation product
  • Cosmetics: retention of the physical qualities of freshly manufactured product, instability that is gauged by its loss of elegance
• Types of Stability Studies

  • Short Term / Accelerated Stability Studies
  • Long Term/Real Time Stability Studies
  • Stress Tests (done on API)
• Short Term / Accelerated Stability Studies

  Involves the use of exaggerated conditions of temperature, light, moisture, pH, humidity, etc., to test the stability of drug formulations. The purpose is to determine kinetic parameters, if possible and/or to predict the tentative expiration dating period
• A suggestion that has been made by the US FDA that shows wide acceptance of this method is as follows: 1. Three months acceptable data at 37 - 40°C/75% R.H. can be extrapolated to a two-year expiry date. 2. If two-year controlled room temperature (R.T.) samples are available, up to two more years could be added to the expiry date (i.e., four years total) by storing the two-year R.T. Samples at 37°C/75% R.H. for three months.
• Significance of Accelerated Stability Studies

  To intensify the degradation loss with time, to enable researchers to predict the shelf life of a product within a short period of time, to determine the most stable formulation for a particular therapeutic actives (in pre formulation studies)
• Long Term/Real Time Stability Studies

  Conducted under the usual / normal conditions of the environment, transport and storage expected during product distribution. It makes use of different "climatic zones" also called Global Assessment of Stability of exposure: Zone 1 – Temperate, Zone 2 – Subtropical, Zone 3 – Hot and dry, Zone 4 – Hot and humid
• Initially, the product is exposed at 25°C/60% R.H. ± 5% allowance. This stability has a duration of at least 2 years. Intermediate Stability studies: 30 +/- 2°C, 60 +/- 5% RH, 6 mos.
• Stress Tests (done on API)

  Involves the use of elevated temperature, in 10 degrees increments higher than those in ASS. This test is performed until the total physical and chemical degradation of the product is reached. This stability testing has a duration of 6-12 months.
• Significance of Stress Tests

  To enable researchers to predict the shelf life of a product, to determine the most stable formulation for a particular therapeutic actives, to serve as basis for assigning storage conditions, to serve as basis for selecting containers, to determine expiration date
• Stability Testing Frequency

  • Long term: 1st yr: every 3 months, 2nd yr: every 6 months, Yearly after
  • Accelerated: Three times points, 0,3, and 6 months
  • Intermediate: Every 3 months for 1 year, If needed as a result of Significant Change
• Storage Temperatures

  • Refrigerator: 2-8°C
  • Controlled Room Temperature: 15-30°C
  • Freezer: -20°C
• Factors that affect product stability

  • Temperature
  • Light
  • PH-level
  • Humidity
  • gravity
  • agitation
  • inversion
  • method and nature of manufacture
  • moisture
• Overage

  The voluntary introduction of a specific excess during the manufacture of pharmaceutical forms of medicaments that are unstable by nature and difficult to stabilize, in order to maintain during their period of use an active content within the limits compatible with therapeutic requirement
• Types of Overage

  • Manufacturing Overage
  • Stability Overage
• Overages are justifiable when: The labile active ingredients cannot possibly be standardized, The overage allows an even equilibrium of the content of the active ingredient within the acceptable limits, The overage would not present a possibility of a therapeutic overdosage if the preparation were used during the early part of the product's shelf life, The clinical studies show that overage is safe therapeutically.
• The proposed rules on overaged for vitamins are: A loss of not more than 10% of the labeled potency is considered normal at the end of the term of validity of the product, Different galenical dosage form is considered separately with a distinction made between simple and complex preparations including a separate study of preparations containing higher doses, The added overage is limited to not more than 30%of the labeled potency of the particular ingredient.
• Allowable Overage

  • Vitamins: up to 30%
  • Drugs: up to 10%
• Predicting Shelf-Life

  The technique of estimating the shelf life of a formulation from its accumulated stability data has evolved from examining the data and making an educated guess through plotting the time temperature points on appropriate graph paper and crudely extrapolating a regression line to the application of vigorous physical chemical laws, statistical concepts and computers to obtain meaningful reliable estimates
• Methods of Predicting Shelf Life

  • Free Hand Method
  • Least Square Method
• Arrhenius Equation

  Used to calculate shelf life based on accelerated stability data
• Least Square Method

  Arrange the data in columns

  2. Compute for the sum of the four values

  3. Solve for a [Potency]

  4. Solve for b [Months]

  5. Assign y = 90

  6. Solve for x (shelf life in months)

  7. Assign the expiration date using the computed shelf life
• Expiration Date = Date of Manufacture + Shelf Life
• Analytical Chemistry

  Science of obtaining, processing, and communicating information about the composition and structure of matter
• Analytical Chemistry

  Art and science of determining what matter is and how much of it exists
• Analytical Chemistry

  Also known as Qualitative-Quantitative Chemistry
• Analytical Chemistry

  A branch of chemistry which provides information relative to the composition of matter
• Assay

  An analysis done to determine: 1. The presence of a substance and the amount of that substance. 2. The biological or pharmacological potency of a drug.
• Classification of Analysis

  • Based on sample size
  • Based on extent of determination/ analysis
  • Based on nature of the analytical method
  • Based on the material used
• Proximate analysis

  Total amount of class or group of active plant principles in a given sample