PF2017 revise

• solubilising agents may cause local irritation
• hyaluronidase can aid absorption in subcut
• iv has no limitation to max vol administered
• drugs in non-aqueous vehicles are mostly administered IM
• suspensions are administered IM or SC
• IV: rapid achievement of concentration, precise delivery of dose, easy to titrate

  but: can lead to toxicity, be invasive, skill is needed to carry out, drug must be in solution
• sc: prompt absorption[tion, no skill, avoids GIT, can be used for suspensions
• IM > SC > oral due to vascularity of muscle and dermis
• IM administers drug into relaxed muscle which must diffuse through epithelial cells and basement membrane. in the absorption step a depot forms and rate of diffusion depends on depth of injection, local blood flow supple and muscle exercise.
• IM: less skill, oily vehicles, prompt absorption, depot

  but: painful, variability in bioavailability, must avoid nerves and vasculature
• antimicrobials


  efficacy is influenced by absorption onto container, ph, concentration, level of contamination

  challenged associated include not all satisfy conditions, toxicity concerns, interactions with components or container
• solubilising, wetting and emulsifying agents

  enhance wetting and maintain solubilisation
• solvents/ vehicles

  propylene glycol -> toxicity, high osmotic pressure, hemolysis, drug precipitation
• non water miscible vehicles


  fixed oils and synthetic esters -> degree of unsaturation and free fatty acid content (must test for free fatty acid, concerns include oil degradation and presence of mineral oil or paraffin)
• non aqueous vehicles


  may enhance drug stability and produce depot effect

  can only be administered IM or SC, can cause pain or tissue necrosis, risk of solidification, contaminate syringe and needle
• minimum freezing temperature should be below the glass transition temperature or collapse temperature if in amorphous state, bellow eutectic temperature if in crystalline state
• large crystals can be achieved by reducing supercooling
• high surface area creates high cake resistance, resulting in a lower primary drying rate and higher secondary drying rate
• low surface area creates low cake resistance, resulting in higher primary drying rate and lower secondary drying rate
• slow freezing has the potential to damage proteins prone to phase separations as it is a kinetic process and slow freezing allows enough time for the process to occur
• freezing is carried out at atmospheric temperature
• product temperature is a function of heap capacity, shelf temp and chamber pressure of freeze dryer
• primary drying is carried out at low temperature to improve rate of ice sublimation, chamber pressure is below ice vapour pressure
• primary drying end point is when the product approached shelf temperature
• glass transition temperature is determined in secondary drying stage
• bulking agents in lyophilised formulations: mannitol, amino acids, albumin
• glass type 1: borosilicate (low leaching, terminal sterilise), type 2: soda-lime-silica (high hydrolytic resistance, dry heat sterilise, aseptic filling), type 3: soda-lime glass (non-parenterals)
• borosilicate glass is used for terminal sterilisation as boron oxide replaces some of the sodium and calcium resulting in glass with exceptional chemical durability and heat resistance
• membrane filtration method


  control 1: broth plus loop of bacteria

  control 2: broth plus sterile WFI

  control 3: broth plus loop of bacteria plus sample of batch
• fluid thioglycollate medium 


  suitable for aerobic and anaerobic mo
• soya bean casein digest or trypticase soy broth


  fungal, yeast, aerobic and anaerobic

  slow growing aerobes

  22.5 +/- 2.5 C
• MF 


  advantages: greater sensitivity, antimicrobial agent can be removed with rinsing, enter contents of container can be testes, low level of contamination, faster results as only 7 days incubation period

  disadvantages: high probability of inadvertent contamination in manual operations because of skill level, unsuitable for unfilterable materials
• sample size depends on

  • number of units in batch
  • vol of liquid per unit
  • method of sterilisation
  • use of biological indicators
  • local GMP
• parametric release is the release of products without end product sterility testing but based on validation of the sterilisation process. usually involves large volume parenterals. validation studies must include heat distribution, heat penetration, bioburden and cycle lethality studies
• test for pyrogens

  1. equipment needs to be pyrogen free - 250 C for 30 mins
  2. warm product to 38.5 C and has to be isotonic
  3. three healthy rabbits of known weight
  4. inject ear vein with 10ml/kg of product
  5. record temperature at 1,2,3 hours
• test for bacterial endotoxins


  LAL test: extra blood cells from horse shoe crab. contains enzyme and protein that with coagulate in presence of LPS. blood is lysed. lysate is purified and freeze dried to yield LAL reagent.

  1. 0.1ml of LAL reagent + 0.1ml of sample
  2. incubate at 37C for 1 hour
  3. check for clot - positive if clot maintains integrity after slow inversion of test tube
• visible particles test


  allen viewer- white and black background with a light that fluoresces particles
• sub visible particles


  light obscuration: light blockage, measure by photodiode, proportional to area of particle, rapid, non destructive, expensive, no identification

  microscope: filter and observe, 1D, identification, skill, accidental contamination
• intraocular injections


  intravitreal injections are the most efficient. they bypass blood-ocular barriers. used for low molecular weight drugs and monoclonal antibodies. 0.05ml - 0.1ml. if steroid injections are administered often it can create an increase in intraocular pressure. risk of retinal detachment, lens detachment, cataract formation
• liposomes


  increased drug activity, prolonged ocular residence, reduced toxicity. verteporfin is indicated for the treatment of wet age related macular degeneration.

  1. inject, uptake by plasma LDL, accumulation in neovasculature
  2. light activated by low energy laser to create singlet oxygen and oxygen radicals
  3. treat leaking vasculature
  4. finished drug product is a lyophilised dark green cake which has to be reconstituted prior to administration