Paren

• Parenteral


  Types of parenteral dosage forms
• Types of parenteral dosage forms

  • Single dose units
  • Multiple dose units
• Multiple dose units based on types of packaging

  • Based on types of packaging
  • Large volume parenterals
  • Small volume parenterals
• Multiple dose units based on production and control

  • Based on the production and control
  • Large volume parenterals
  • Small volume parenterals
• Quality Assurance


  The planned and systematic activities implemented in a quality system so that quality requirements for a product or service will be fulfilled
• Quality Control


  The procedure or set of procedures intended to ensure that a manufactured product or performed service adheres to a defined set of quality criteria or meets the requirements of the client or customer
• IPQC


  Controlling the procedures involved in manufacturing of the dosage forms starting from raw materials purchase to dispatch of the quality product in ideal packaging

  
• IPQC


  • Monitors all the features of the product that may affect its quality and prevents errors during processing
• Leaker test


  1. Detect incompletely sealed ampules

  2. Submerge ampules in dye solution

  3. Apply vacuum to detect leaks

  4. Inspect for dye penetration

  
• Vacuum test for vials/bottles


  Detect presence of vacuum by striking base and checking for water hammer sound or using spark tester
• Dye test


  1. Immerse container in dye bath

  2. Apply vacuum/pressure

  3. Remove and wash container

  4. Inspect for dye penetration

  
• Dye test


  • Inexpensive, no special equipment, qualitative, destructive, slow
• Considerations for pH of formulation


  • Effect on the body when administered
  • Effect on stability of the product
  • Effect on container-closure system
• Sterility testing


  Carried out under aseptic conditions to avoid contamination
• All glassware required for sterility testing must be sterile
• Media used in sterility testing

  • Soybean Casein Digest Medium for Streptococcus species
  • Fluid Thioglycolate Medium for Clostridium species
• Fluid Thioglycolate Medium (FTM)


  Provides both aerobic and anaerobic environments, neutralizes bacteriostatic properties of preservatives
• Soya-bean casein digest medium


  Primarily intended for the culture of both fungi and aerobic bacteria
• Membrane filtration


  1. Sterilize filtration system

  2. Filter sample through 0.45μ membrane

  3. Incubate membrane halves in media
• Membrane filters


  Cellulose nitrate for aqueous, oily, weakly alcoholic solutions

  Cellulose acetate for strongly alcoholic solutions

  Specially adapted filters may be needed for certain products like antibiotics
• Membrane filtration


  • Allows aseptic removal of membrane for transfer to media

  Allows incubation after adding media to apparatus
• Many membrane filters allow viruses and some mycoplasmas to pass through, and may absorb filtrate and introduce metallic ions
• Direct inoculation method


  Traditional sterility test method involving direct inoculation of sample into culture media
• Direct inoculation method


  1. Remove sample aseptically

  2. Transfer to culture media

  3. Incubate for 14 days

  4. Observe for microbial growth
• Interpretation of direct inoculation results

  No growth = pass, Growth = retest, Confirmed growth = fail
• Interpretation of results (sterility test)

  1. No evidence of growth - preparation passes sterility test

  2. Evidence of growth - retest with same number of samples

  3. No evidence of growth in retest - preparation passes sterility test

  4. Evidence of growth in retest - isolate and identify organisms, if not distinguishable from first test then preparation fails sterility test, if distinguishable then retest with twice the number of samples, if no growth then preparation passes sterility test, if growth then preparation fails sterility test

  
• Direct inoculation method (interpretation of results)

  Evidence of microbial growth - isolate and identify organisms, if not distinguishable from first test then preparation fails sterility test, if distinguishable then retest with twice the number of samples, if no growth then preparation passes sterility test, if growth then preparation fails sterility test
• Biological Indicators (BIs)


  Widely used to monitor the efficacy of sterilization processes, provide a high level of sterility assurance, ideal monitors of the sterilization process

  
• Biological Indicator Sterility Test

  Performed on exposed BIs after completion of a sterilization load through either a validation or routine lot release monitoring, qualitative test that yields results of either growth or no growth of the appropriate indicator organism, performed on BIs subjected to different types of sterilization

  
• Biological indicators (BIs) are the most accepted means of monitoring the sterilization process because they directly determine whether the most resistant microorganisms (e.g., Geobacillus or Bacillus species) are present rather than merely determine whether the physical and chemical conditions necessary for sterilization are met

  
• Bacterial pyrogens


  Called "Endotoxins", gram negative bacteria produce more potent endotoxins than gram + bacteria and fungi, heat stable lipopolysaccharides (LPS) present in bacterial cell walls, not present in cell-free bacterial filtrates
• Sources of endotoxins


  • Water (main)
  • Raw materials
  • Equipment
  • Process environment
  • People
  • Protein expression systems if using gram negative bacteria
• Other sources of endotoxins

  • Equipment
  • Containers (Glass, plastic, metal)
  • Solvent
  • Solute
• Ultrafiltration (UF)


  Excellent way of removing pyrogen contamination from water, ultrafilters (positively charged nylon 66 membranes) recommended for final "polishing" of water already treated by deionization (DI) or reverse osmosis RO, remove most organics over 1,000 weight-average molecular weight, such as pyrogens

  
• Methods for elimination of pyrogens

  • Reverse osmosis
  • Distillation
  • Adsorption
• QFRIR (also known as "rabbit test")


  Designed to limit to an unacceptable level the risks of febrile reactions in the patient to the administration or injection of a product, involves measuring the rise in temperature of rabbits following administration of a test solution
• Test Animals (QFRIR)


  • Uses three healthy mature rabbits whose body temperature does not vary by more than 1oC from each other, do not use any rabbit having a temperature exceeding 39.8C
• Sham test (QFRIR)


  If animals are used for the first time in a pyrogen test or have not been used during the 2 previous weeks, condition them 1 to 3 days before testing the substance by injecting IV 10mL per kg pyrogen free saline solution warmed to about 38.5C, record the temperature of the animals beginning at least 90 min before injection and continuing for 3h after injection, any animal showing temperature variation of 0.6C or more must not be used in main test
• Procedure (QFRIR)


  Get the baseline temperature of the rabbits, inject into an ear vein 10mL/kg of the test solution, in portions, completing each injection within 10 minutes after start of administration, record the temperature after 1 hour, 2 hours and 3 hours, observe the rise in temperature
• Interpretation criteria (QFRIR)


  • Accept if no rabbit shows an individual rise in temperature that is >= 0.6oC [0.5oC] and sum of the three individual temperature rise should not exceed 1.4oC, reject if more than 3 of the 8 rabbits showed a temperature rise of >= 0.6oC [0.5oC] or sum of the readings of temperature rise for the 8 rabbits is more than 3 3oC